metabolic disorders in patients with chronic kidney … · metabolic disorders in patients with...
TRANSCRIPT
Metabolic disorders in patients with chronic kidney failure
Roman Cibulka Jaroslav Racek
Institute of Clinical Biochemistry and Hematology Charles University Medical Faculty and Faculty
Hospital in Pilsen Czech Republic
Corresponding author MUDr Roman Cibulka
Charles University Hospital in Pilsen
Institute of Clinical Biochemistry and Hematology
Alej Svobody 80
304 60 Plzeň
Czech Republic
E-mail cibulkarfnplzencz
Short title Metabolic disorders in CKF
Summary
This review article summarizes the problems of metabolic disorders and nutrition imbalances that
often occur in chronic kidney failure or following regular dialysis treatment In this paper we cover
the pathogenesis of these disorders their clinical consequences and their association with the most
severe complications of chronic kidney failure and dialysis treatment These complications are
primarily atherosclerosis malnutrition anemia hyperparathyroidism and other serious problems
that markedly and negatively affect prognosis and the quality of life of uremic patients Risk factors
for cardiovascular disease are discussed in-depth because cardiovascular disease is the leading
cause of death in patients with chronic kidney failure It is important to give attention to the
development of these complications because early diagnosis and therapy can improve prognosis for
these patients and reduce treatment costs
Key words metabolic disorders chronic kidney failure dialysis cardiovascular disease
Introduction
Chronic kidney disease (CKD) is a very real and growing problem as indicated by
demographic trends The total number of treated patients has markedly increased during the last 30
years and CKD currently affects approximately 19 million adult Americans with an incidence that
is increasing rapidly (Snyder and Pendergraph 2005) This trend is caused by a growing percentage
of elderly people in the population as well as by technical progress and broader availability of
dialysis therapy An increasing number of diabetic patients is also an important factor
CKD is characterized by progressive deterioration of kidney function which develops
eventually into a terminal stage of chronic kidney failure (CKF) CKF has traditionally been
categorized as mild moderate or severe Other poorly defined terms like uremia and end-stage
renal disease (ESRD) have commonly been applied During the last few years an international
consensus has emerged categorizing CKF into 5 stages according to the glomerular filtration rate
(GFR) and presence of signs of kidney damage stage 1 GFR gt 90 mlmin and signs of kidney
damage stage 2 GFR = 60ndash89 mlmin and signs of kidney damage stage 3 GFR = 30ndash59 mlmin
stage 4 GFR = 15ndash29 mlmin and stage 5 GFR lt 15 mlmin (Levey et al 2005)
Stage 5 represents the total inability of kidneys to maintain homeostasis and this metabolic
state is incompatible with life Thus at this stage it is necessary to use methods that substitute for
kidney function to ensure patient survival these methods include peritoneal dialysis hemodialysis
and other extracorporeal purifying procedures or kidney transplantation
CKF is associated with many kinds of metabolic changes caused by the kidney disease and
also attributable to dialysis treatment Phenomena such as accumulation or deficit of various
substances and dysregulation of metabolic pathways combine in the pathogenesis of these changes
(Cibulka et al 2005) In the process of accumulation decreased urinary excretion plays a crucial
role and leads to retention of metabolites in the organism (eg creatinine urea electrolytes water)
The increased formation of metabolites through catabolic processes and alternative metabolic
pathways also wields an influence Regular dialysis treatment partly decreases this accumulation
but cannot avert the overall deficit
This deficit of some important substances in CKF can be caused by deficient intake in diet
impaired intestinal absorption or increased losses during dialysis sessions Disturbed synthesis of
some crucial metabolic regulators (eg erythropoietin active vitamin D) in kidneys also plays an
important role
All of the abovementioned factors lead to many serious complications for CKD patients
during the course of predialysis and dialysis All accelerate development of atherosclerosis
malnutrition-inflammation complex syndrome (MICS) anemia hyperparathyroidism and other
serious problems that markedly affect prognosis and the quality of life of patients with CKF
(Cibulka et al 2005 Lindner et al 1974 Durak et al 1994 Silver 2000)
Metabolic disorders in CKF
Acidndashbase balance
Acidndashbase disorder is commonly observed in the course of CKF Metabolic acidosis is noted
in a majority of patients when GFR decreases to less than 20 to 25 of normal The degree of
acidosis approximately correlates with the severity of CKF and usually is more severe at a lower
GFR Metabolic acidosis can be of the high-anion-gap variety although anion gap can be normal or
only moderately increased even with stage 4 or 5 CKF (Kraut and Kurtz 2005) In mild chronic
renal insufficiency metabolic acidosis is the result of a reduced ability to reabsorb bicarbonate to
excrete ammonia and to eliminate titratable acid excretion (hyperchloremic normal anion gap
acidosis) In more severe renal insufficiency organic and other conjugate anions of acids
(nonvolatile acids) cannot be sufficiently excreted and elevated anion gap acidosis appears
(Kovacic et al 2003) Acidosis resulting from advanced renal insufficiency is called uremic
acidosis The level of GFR at which uremic acidosis develops varies depending on a multiplicity of
factors Endogenous acid production is an important factor which in turn depends on the diet
Ingestion of vegetables and fruits results in net production of alkali and therefore increased
ingestion of these foods will tend to delay the appearance of metabolic acidosis in chronic renal
failure Diuretic therapy and hypokalemia which tend to stimulate ammonia production may delay
the development of acidosis The etiology of the renal disease also plays a role In predominantly
tubulointerstitial renal diseases acidosis tends to develop earlier in the course of renal insufficiency
than in predominantly glomerular diseases In general metabolic acidosis is rare when the GFR is
greater than 25ndash20 mlmin (Oh et al 2004)
Several adverse consequences have been associated with uremic acidosis including muscle
wasting bone disease abnormalities in growth hormone and thyroid hormone secretion impaired
insulin sensitivity and exacerbation of beta-2 microglobulin accumulation (Kraut and Kurtz 2005)
Other complications include negative nitrogen balance anorexia fatigue impaired function of the
cardiovascular system hyperkalemia and altered gluconeogenesis and triglyceride metabolism
(Kovacic et al 2003)
Therapy of uremic acidosis should aim to obtain a serum bicarbonate level as close to normal
as possible (ie 22ndash26 mmoll) The best way to initiate therapy is with oral sodium bicarbonate (1
tablet three times a day) and to increase the dosage as necessary The usual tablet of 650 mg of
sodium bicarbonate contains 75 mmol of alkali (HCO3- ions) Occasionally patients experience
gastric discomfort with sodium bicarbonate may use Shohlrsquos solution (a mixture of sodium citrate
and citric acid) In dialysis patients treatment of acidosis relies on the gain of alkali from the
dialysate either as bicarbonate in hemodialysis or as lactate in peritoneal dialysis (Oh et al 2004)
Protein metabolism
A too-strict low-protein diet can have a negative effect on nitrogen balance in the predialysis
period A safe low-protein diet should contain 06 g of proteinkgday minimally Disorders in
protein metabolism in the dialysis period are usually caused by combined (protein and energy)
malnutrition that can be termed uremic malnutrition It is present in approximately 20ndash50 of
patients on dialysis and is characterized by insidious loss of somatic protein stores (reflected in lean
body mass and serum creatinine) and visceral protein concentrations (reflected in serum albumin
and prealbumin concentrations) (Ikizler 2004) Urinary losses of protein and losses of amino acids
during a dialysis session may play a role as well Metabolic acidosis is an important factor that
markedly contributes to negative nitrogen and total body protein balance in CKF (Kovacic et al
2003 Mehrotra et al 2003) It has been demonstrated that the presence of uremic malnutrition
increases mortality and morbidity in chronic dialysis patients (Kopple 1994 Ikizler et al 1999) It
is very often combined with a chronic inflammation state in the syndrome known as MICS
(Kalantar-Zadeh et al 2003)
Carbohydrate metabolism
Disorders of carbohydrate metabolism are also very frequent in CKD Diabetics represent
about 35 of all patients on dialysis therapy Generally non-diabetic CKD patients often also have
glucose intolerance probably because of peripheral insulin resistance (Alvestrand 1997) Insulin
resistance is primarily detectable when the GFR is below 50 mlmin Reduced insulin-mediated
non-oxidative glucose disposal is the most evident defect of glucose metabolism but impairments
of glucose oxidation the defective suppression of endogenous glucose production and abnormal
insulin secretion also contribute to uremic glucose intolerance (Rigalleau and Gin 2005)
Accumulating nitrogenous uremic toxins seem to be the dominant cause of a specific defect in
insulin action and identification of these toxins is progressing particularly in the field of
carbamoylated amino acids The consequences of CKF such as exercise intolerance anemia
metabolic acidosis secondary hyperparathyroidism or vitamin D deficiency also indirectly play a
role (Rigalleau and Gin 2005 Rasic-Milutinovic et al 2000) It has been reported that insulin
resistance may be related to arterial hypertension (Ferrannini et al 1987) and may contribute to
high cardiovascular morbidity and mortality in patients with CKF (Shoji et al 2001 Shinohara et
al 2002) The underlying mechanism can be an impaired synthesis of nitric oxide (NO) in
endothelium of patients with CKD It was reported that appropriately functioning endothelial NO
synthase (eNOS) is important for the control not only of arterial pressure but also of glucose and
lipid homeostasis (Duplain et al 2001)
Lipid metabolism
Serum triglycerides (TG) are elevated in CKF because of enhanced production of TG-rich
lipoproteins such as very-low-density lipoproteins (VLDL) in the liver (Attman et al 1993) and
also because of dysfunction of TG degradation resulting from insufficient mitochondrial beta-
oxidation of fatty acids It can be caused by a deficit of L-carnitine which is frequently present
especially in hemodialysis (HD) patients (Cibulka et al 2005 Guarnieri et al 1992)
Hyperinsulinemia is the main factor increasing synthesis of TG and also directly decreases activity
of lipoprotein lipase The following changes in lipid metabolism are also found in many patients
with CKF The most prominent are increased serum TG levels and low levels of high-density
lipoprotein (HDL) cholesterol Low-density lipoprotein (LDL) cholesterol levels are often normal
but the cholesterol may originate from the atherogenic small and dense LDL subclass The
apolipoprotein B-containing part of the lipoprotein may undergo modifications (peptide
modification of the enzymatic and advanced glycation end-product oxidation or glycation)
Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote
prolonged circulation HDL particles are structurally altered during states of inflammation The
contribution of this complex and the atherogenic form of dyslipidemia to cardiovascular disease
(CVD) in patients with renal disease is at present unclear
Some studies report negative results regarding the predictive power of serum lipids for the
development of CVD (Wanner and Krane 2002) Recent findings have suggested that the
development of MICS is responsible for this phenomenon Because MICS leads to a low body mass
index hypocholesterolemia hypocreatininemia hypohomocysteinemia and other manifestations a
reverse epidemiology of traditional cardiovascular risk factors occurs in CKF Therefore
hypercholesterolemia obesity and increased blood levels of creatinine and homocysteine appear to
be protective and paradoxically associated with a better outcome in patients with CKF (Kalantar-
Zadeh et al 2003 Kalantar-Zadeh et al 2005)
It is well known that HDL cholesterol levels are inversely correlated with the risk of
atherosclerosis In addition to its role in reverse cholesterol transport HDL has the ability to protect
LDL particles against oxidation The underlying mechanism by which HDL inhibits LDL oxidation
is partly enzymatic There is increasing evidence that paraoxonase 1 (PON1) could be involved in
this process (Mackness et al 1993) It was proved that serum PON1 activity is reduced in CKF
patients The possible causes can include reduced HDL levels altered HDL subfraction distribution
reduced PON1 concentration and different PON1 phenotype distributions Another possible
explanation could be that PON1 activity is inhibited in the uremic environment Generally reduced
serum PON1 activity could also contribute to the accelerated development of atherosclerosis in
CKF patients (Dirican et al 2004)
Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for atherosclerotic
CVD It was found to be consistently elevated in a considerable proportion of CKD patients Plasma
concentrations of Lp(a) are highly heritable and mainly determined by a size polymorphism of
apolipoprotein(a) [Apo(a)] It has been demonstrated that the low-molecular-weight Apo(a)
phenotype independently predicted coronary artery disease occurrence in a cohort of 440 unselected
HD patients in a prospective study over five years (Kronenberg et al 1999) It has been suggested
that the Apo(a) size and the Lp(a) plasma concentration may play a synergistic role in advanced
atherosclerosis
Because kidneys perform important hormonal functions there are also some serious
complications associated with a lack of important metabolic hormonal regulators in the course of
CKF The major problems are primarily renal anemia and renal bone disease (renal osteodystrophy)
Renal anemia
Renal anemia which is often associated with fatigue and cognitive and sexual dysfunction
has a significant impact on the quality of life of patients with CKF Anemia has also been identified
as an important etiologic factor in the development of left ventricular hypertrophy an independent
risk factor for heart failure and a predictor of mortality in HD patients (Golper et al 2003) The
major cause of renal anemia in CKF is an inadequate production of the glycoprotein hormone
erythropoietin (EPO) because of a reduction in functional kidney parenchyma (Santoro 2002)
Furthermore free radicals elicited from leucocytes by their contact with the dialysis membrane
cause hemolysis with consecutive anemia in CKF patients on extracorporeal renal replacement
therapy (Eiselt et al 1999)
There are a number of other metabolic derangements associated with uremia that can affect
the production and survival of red blood cells (eg some uremic toxins parathormone protein
malnutrition) (Golper et al 2003 Eschbach and Adamson 1985) The introduction of recombinant
human EPO (rHuEPO) has revolutionized the treatment of anemia in CKF The vast majority of
patients respond very well to treatment but 5ndash10 of patients show some resistance to rHuEPO
the most common causes of which are considered iron deficiency (Santoro 2002) and the
development of MICS (Kalantar-Zadeh et al 2003) The EPO hyporesponsiveness can further
worsen symptoms that decrease the quality of life such as an intolerance of physical work
deterioration of cognitive functions anorexia insomnia or depression These problems are partly
related to the deficit of L-carnitine in HD patients (dialysis-related carnitine disorder) This disorder
is a functional metabolic deficiency common in chronic HD patients and can have a negative impact
on erythrocyte production and survival Laboratory studies examining the influence of carnitine on
red blood cell function and clinical trials in HD patients support the use of L-carnitine in the setting
of rHuEPO hyporesponsiveness (Golper et al 2003)
Renal osteodystrophy
Renal osteodystrophy which is the term used to describe the skeletal abnormalities of many
CKD patients is a multifactorial disorder of bone remodeling It encompasses a heterogeneous
group of disorders from states of high bone turnover to states of low bone turnover High-turnover
bone disease or osteitis fibrosa represents the manifestations of secondary hyperparathyroidism
(SHPT) on bone Low bone turnover syndromes are represented by the increasingly prevalent
adynamic bone or less commonly by osteomalacia These disorders may occur in combination or
alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most
important factor which is probably responsible for SHPT development is a deficit of active vitamin
D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is
a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the
small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this
situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting
hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and
subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this
harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one
or more of them may predominate in a particular patient during the course of CKF much overlap
occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an
important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular
calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)
The treatment of vitamin D deficiency when present in CKD patients is warranted since such
therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of
20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by
supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended
daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in
stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in
dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the
serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used
to treat vitamin D deficiency (National Kidney Foundation 2004)
Cardiovascular disease
CVD is the leading cause of death in patients with CKF For every registry reporting national
dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD
(Foley et al 1998) In comparison with the general population dialysis patients have a greater than
20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these
deaths are related to vascular occlusive disease with associated myocardial infarction
cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with
CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis
and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion
to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin
The evidence suggests that the damage is already far progressed when patients reach ESRD thus
effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with
albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional
risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential
(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)
recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin
concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than
1 g of protein24 hours (National Kidney Foundation 2002)
The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL
cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)
However as mentioned above some CKD patients with the lowest cholesterol levels are the most
likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac
risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)
Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism
uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et
al 1999)
Oxidative stress
Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds
the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly
reactive substances with an unpaired electron in the outer orbital and other related reactive
compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and
nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998
Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and
consequently are not recognized by cell LDL receptors They are subsequently accumulated in the
blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of
atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications
(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of
chronic inflammation) Free radicals originate from leucocytes which are activated during the
contact with the dialysis membrane and also from erythrocyte iron released as a consequence of
hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of
EPO treatment can also contribute to oxidative stress increasing free radical production by the so-
called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of
mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions
to more dangerous Fe(II) compounds (Eiselt et al 2006)
Dialysis-related amyloidosis
Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal
replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA
Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel
syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular
pathogenesis of this complication remains unknown Recent studies however have suggested a
pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased
carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in
uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation
end-product production Thus uremia might be a state of carbonyl overload with potentially
damaging proteins (carbonyl stress) (Miyata et al 1999)
Hyperhomocysteinemia and endothelial dysfunction
Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma
concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The
causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a
result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is
considered to be an independent risk factor for the development of CVD As mentioned above
reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased
Hcy levels appear to be paradoxically associated with a better clinical outcome The development of
MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration
is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy
was inversely correlated with subjective global nutritional assessment and positively correlated with
serum albumin and protein intake Thus serum albumin concentration is a strong determinant of
plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished
patients (Suliman et al 2001)
On the other hand the toxicity of Hcy results from the structural modification of proteins and
DNA Disruption of DNA methylation has been demonstrated to occur as a result of
hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a
principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may
impair endothelial function by the generation of oxygen species and decreased NO bioavailability
Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system
in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic
et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis
endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation
(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of
the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise
mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function
in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation
of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing
connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly
by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are
elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)
In some studies an increased level of ADMA has been identified as an independent predictor of
mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function
in CRF may offer a novel strategy to reduce CVD
Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately
it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney
Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with
risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years
and family history of CKD When CKD is detected an attempt should be made to identify and treat
the underlying conditions as well as the secondary abnormalities These goals include slowing
disease progression detecting and treating complications and managing cardiovascular risk factors
Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition
anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase
balance At the same time it is necessary to continue research projects focused on other areas that
may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas
include the development of MICS management of oxidative stress and endothelium protection
Clearly progress in management of CVD in patients with CKD will require collaboration with
experts in the research and treatment of vascular disease
Conclusion
CKD leading to CKF is an urgent medical problem in the context of demographic trends In
addition to the basic kidney disease many metabolic disorders develop in the course of CKF
Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment
decreases the accumulation of metabolites however it contributes to a deficit of some important
metabolic regulators and to the development of a chronic inflammation state These factors can lead
to serious secondary complications in CKF including atherosclerosis and related cardiovascular
disease malnutrition anemia renal bone disease and other problems These complications
markedly and negatively affect the prognosis and quality of life of patients with CKF and increase
costs for their treatment The prognosis of CKD patients can be improved if kidney disease is
diagnosed early and properly cured inclusive of the secondary complications Appropriate
treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and
hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for
kidney disease and to develop new therapeutic methods to improve the quality of life of CKD
patients At the same time we must try to reduce economic costs connected with treatment
Acknowledgments
This work was supported by the research project MSM 0021620819
References
ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52
1997
ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am
J Kidney Dis 21 573-592 1993
CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal
failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005
DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33
2005
DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several
potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003
DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of
chronic kidney disease Hemodial Int 10 42-48 2006
DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic
predialysis and hemodialysis patients J Nephrol 17 813-818 2004
DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P
PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and
hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001
DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte
defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66
76-80 1994
EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on
oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in
Press
EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy
Vnitr Lek 45 319-324 1999
ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985
FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M
GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential
hypertension N Engl J Med 317 350-357 1987
FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in
chronic renal disease Am J Kidney Dis 32 S112-S119 1998
GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular
calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005
GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the
risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004
GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J
Kidney Dis 41 (4 Suppl 4) S27-S34 2003
GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193
2001
GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-
carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis
patients Contrib Nephrol 98 36-43 1992
IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity
with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study
Kidney Int 55 1945-1951 1999
IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic
dialysis patients Semin Dial 17 471-478 2004
KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-
inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis
42 864-881 2003
KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M
COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation
Curr Opin Clin Nutr Metab Care 8 388-396 2005
KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON
DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health
Perspect 1 289-295 1998
KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997
KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J
Kidney Dis 24 1002-1009 1994
KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed
patients Am J Nephrol 23 158-164 2003
KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and
treatment Am J Kidney Dis 45 978-993 2005
KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A
MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an
independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up
J Am Soc Nephrol 10 1027-1036 1999
LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D
HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney
disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney
Int 67 2089-2100 2005
LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial
Transplant 14 828-833 1999
LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving
intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
Summary
This review article summarizes the problems of metabolic disorders and nutrition imbalances that
often occur in chronic kidney failure or following regular dialysis treatment In this paper we cover
the pathogenesis of these disorders their clinical consequences and their association with the most
severe complications of chronic kidney failure and dialysis treatment These complications are
primarily atherosclerosis malnutrition anemia hyperparathyroidism and other serious problems
that markedly and negatively affect prognosis and the quality of life of uremic patients Risk factors
for cardiovascular disease are discussed in-depth because cardiovascular disease is the leading
cause of death in patients with chronic kidney failure It is important to give attention to the
development of these complications because early diagnosis and therapy can improve prognosis for
these patients and reduce treatment costs
Key words metabolic disorders chronic kidney failure dialysis cardiovascular disease
Introduction
Chronic kidney disease (CKD) is a very real and growing problem as indicated by
demographic trends The total number of treated patients has markedly increased during the last 30
years and CKD currently affects approximately 19 million adult Americans with an incidence that
is increasing rapidly (Snyder and Pendergraph 2005) This trend is caused by a growing percentage
of elderly people in the population as well as by technical progress and broader availability of
dialysis therapy An increasing number of diabetic patients is also an important factor
CKD is characterized by progressive deterioration of kidney function which develops
eventually into a terminal stage of chronic kidney failure (CKF) CKF has traditionally been
categorized as mild moderate or severe Other poorly defined terms like uremia and end-stage
renal disease (ESRD) have commonly been applied During the last few years an international
consensus has emerged categorizing CKF into 5 stages according to the glomerular filtration rate
(GFR) and presence of signs of kidney damage stage 1 GFR gt 90 mlmin and signs of kidney
damage stage 2 GFR = 60ndash89 mlmin and signs of kidney damage stage 3 GFR = 30ndash59 mlmin
stage 4 GFR = 15ndash29 mlmin and stage 5 GFR lt 15 mlmin (Levey et al 2005)
Stage 5 represents the total inability of kidneys to maintain homeostasis and this metabolic
state is incompatible with life Thus at this stage it is necessary to use methods that substitute for
kidney function to ensure patient survival these methods include peritoneal dialysis hemodialysis
and other extracorporeal purifying procedures or kidney transplantation
CKF is associated with many kinds of metabolic changes caused by the kidney disease and
also attributable to dialysis treatment Phenomena such as accumulation or deficit of various
substances and dysregulation of metabolic pathways combine in the pathogenesis of these changes
(Cibulka et al 2005) In the process of accumulation decreased urinary excretion plays a crucial
role and leads to retention of metabolites in the organism (eg creatinine urea electrolytes water)
The increased formation of metabolites through catabolic processes and alternative metabolic
pathways also wields an influence Regular dialysis treatment partly decreases this accumulation
but cannot avert the overall deficit
This deficit of some important substances in CKF can be caused by deficient intake in diet
impaired intestinal absorption or increased losses during dialysis sessions Disturbed synthesis of
some crucial metabolic regulators (eg erythropoietin active vitamin D) in kidneys also plays an
important role
All of the abovementioned factors lead to many serious complications for CKD patients
during the course of predialysis and dialysis All accelerate development of atherosclerosis
malnutrition-inflammation complex syndrome (MICS) anemia hyperparathyroidism and other
serious problems that markedly affect prognosis and the quality of life of patients with CKF
(Cibulka et al 2005 Lindner et al 1974 Durak et al 1994 Silver 2000)
Metabolic disorders in CKF
Acidndashbase balance
Acidndashbase disorder is commonly observed in the course of CKF Metabolic acidosis is noted
in a majority of patients when GFR decreases to less than 20 to 25 of normal The degree of
acidosis approximately correlates with the severity of CKF and usually is more severe at a lower
GFR Metabolic acidosis can be of the high-anion-gap variety although anion gap can be normal or
only moderately increased even with stage 4 or 5 CKF (Kraut and Kurtz 2005) In mild chronic
renal insufficiency metabolic acidosis is the result of a reduced ability to reabsorb bicarbonate to
excrete ammonia and to eliminate titratable acid excretion (hyperchloremic normal anion gap
acidosis) In more severe renal insufficiency organic and other conjugate anions of acids
(nonvolatile acids) cannot be sufficiently excreted and elevated anion gap acidosis appears
(Kovacic et al 2003) Acidosis resulting from advanced renal insufficiency is called uremic
acidosis The level of GFR at which uremic acidosis develops varies depending on a multiplicity of
factors Endogenous acid production is an important factor which in turn depends on the diet
Ingestion of vegetables and fruits results in net production of alkali and therefore increased
ingestion of these foods will tend to delay the appearance of metabolic acidosis in chronic renal
failure Diuretic therapy and hypokalemia which tend to stimulate ammonia production may delay
the development of acidosis The etiology of the renal disease also plays a role In predominantly
tubulointerstitial renal diseases acidosis tends to develop earlier in the course of renal insufficiency
than in predominantly glomerular diseases In general metabolic acidosis is rare when the GFR is
greater than 25ndash20 mlmin (Oh et al 2004)
Several adverse consequences have been associated with uremic acidosis including muscle
wasting bone disease abnormalities in growth hormone and thyroid hormone secretion impaired
insulin sensitivity and exacerbation of beta-2 microglobulin accumulation (Kraut and Kurtz 2005)
Other complications include negative nitrogen balance anorexia fatigue impaired function of the
cardiovascular system hyperkalemia and altered gluconeogenesis and triglyceride metabolism
(Kovacic et al 2003)
Therapy of uremic acidosis should aim to obtain a serum bicarbonate level as close to normal
as possible (ie 22ndash26 mmoll) The best way to initiate therapy is with oral sodium bicarbonate (1
tablet three times a day) and to increase the dosage as necessary The usual tablet of 650 mg of
sodium bicarbonate contains 75 mmol of alkali (HCO3- ions) Occasionally patients experience
gastric discomfort with sodium bicarbonate may use Shohlrsquos solution (a mixture of sodium citrate
and citric acid) In dialysis patients treatment of acidosis relies on the gain of alkali from the
dialysate either as bicarbonate in hemodialysis or as lactate in peritoneal dialysis (Oh et al 2004)
Protein metabolism
A too-strict low-protein diet can have a negative effect on nitrogen balance in the predialysis
period A safe low-protein diet should contain 06 g of proteinkgday minimally Disorders in
protein metabolism in the dialysis period are usually caused by combined (protein and energy)
malnutrition that can be termed uremic malnutrition It is present in approximately 20ndash50 of
patients on dialysis and is characterized by insidious loss of somatic protein stores (reflected in lean
body mass and serum creatinine) and visceral protein concentrations (reflected in serum albumin
and prealbumin concentrations) (Ikizler 2004) Urinary losses of protein and losses of amino acids
during a dialysis session may play a role as well Metabolic acidosis is an important factor that
markedly contributes to negative nitrogen and total body protein balance in CKF (Kovacic et al
2003 Mehrotra et al 2003) It has been demonstrated that the presence of uremic malnutrition
increases mortality and morbidity in chronic dialysis patients (Kopple 1994 Ikizler et al 1999) It
is very often combined with a chronic inflammation state in the syndrome known as MICS
(Kalantar-Zadeh et al 2003)
Carbohydrate metabolism
Disorders of carbohydrate metabolism are also very frequent in CKD Diabetics represent
about 35 of all patients on dialysis therapy Generally non-diabetic CKD patients often also have
glucose intolerance probably because of peripheral insulin resistance (Alvestrand 1997) Insulin
resistance is primarily detectable when the GFR is below 50 mlmin Reduced insulin-mediated
non-oxidative glucose disposal is the most evident defect of glucose metabolism but impairments
of glucose oxidation the defective suppression of endogenous glucose production and abnormal
insulin secretion also contribute to uremic glucose intolerance (Rigalleau and Gin 2005)
Accumulating nitrogenous uremic toxins seem to be the dominant cause of a specific defect in
insulin action and identification of these toxins is progressing particularly in the field of
carbamoylated amino acids The consequences of CKF such as exercise intolerance anemia
metabolic acidosis secondary hyperparathyroidism or vitamin D deficiency also indirectly play a
role (Rigalleau and Gin 2005 Rasic-Milutinovic et al 2000) It has been reported that insulin
resistance may be related to arterial hypertension (Ferrannini et al 1987) and may contribute to
high cardiovascular morbidity and mortality in patients with CKF (Shoji et al 2001 Shinohara et
al 2002) The underlying mechanism can be an impaired synthesis of nitric oxide (NO) in
endothelium of patients with CKD It was reported that appropriately functioning endothelial NO
synthase (eNOS) is important for the control not only of arterial pressure but also of glucose and
lipid homeostasis (Duplain et al 2001)
Lipid metabolism
Serum triglycerides (TG) are elevated in CKF because of enhanced production of TG-rich
lipoproteins such as very-low-density lipoproteins (VLDL) in the liver (Attman et al 1993) and
also because of dysfunction of TG degradation resulting from insufficient mitochondrial beta-
oxidation of fatty acids It can be caused by a deficit of L-carnitine which is frequently present
especially in hemodialysis (HD) patients (Cibulka et al 2005 Guarnieri et al 1992)
Hyperinsulinemia is the main factor increasing synthesis of TG and also directly decreases activity
of lipoprotein lipase The following changes in lipid metabolism are also found in many patients
with CKF The most prominent are increased serum TG levels and low levels of high-density
lipoprotein (HDL) cholesterol Low-density lipoprotein (LDL) cholesterol levels are often normal
but the cholesterol may originate from the atherogenic small and dense LDL subclass The
apolipoprotein B-containing part of the lipoprotein may undergo modifications (peptide
modification of the enzymatic and advanced glycation end-product oxidation or glycation)
Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote
prolonged circulation HDL particles are structurally altered during states of inflammation The
contribution of this complex and the atherogenic form of dyslipidemia to cardiovascular disease
(CVD) in patients with renal disease is at present unclear
Some studies report negative results regarding the predictive power of serum lipids for the
development of CVD (Wanner and Krane 2002) Recent findings have suggested that the
development of MICS is responsible for this phenomenon Because MICS leads to a low body mass
index hypocholesterolemia hypocreatininemia hypohomocysteinemia and other manifestations a
reverse epidemiology of traditional cardiovascular risk factors occurs in CKF Therefore
hypercholesterolemia obesity and increased blood levels of creatinine and homocysteine appear to
be protective and paradoxically associated with a better outcome in patients with CKF (Kalantar-
Zadeh et al 2003 Kalantar-Zadeh et al 2005)
It is well known that HDL cholesterol levels are inversely correlated with the risk of
atherosclerosis In addition to its role in reverse cholesterol transport HDL has the ability to protect
LDL particles against oxidation The underlying mechanism by which HDL inhibits LDL oxidation
is partly enzymatic There is increasing evidence that paraoxonase 1 (PON1) could be involved in
this process (Mackness et al 1993) It was proved that serum PON1 activity is reduced in CKF
patients The possible causes can include reduced HDL levels altered HDL subfraction distribution
reduced PON1 concentration and different PON1 phenotype distributions Another possible
explanation could be that PON1 activity is inhibited in the uremic environment Generally reduced
serum PON1 activity could also contribute to the accelerated development of atherosclerosis in
CKF patients (Dirican et al 2004)
Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for atherosclerotic
CVD It was found to be consistently elevated in a considerable proportion of CKD patients Plasma
concentrations of Lp(a) are highly heritable and mainly determined by a size polymorphism of
apolipoprotein(a) [Apo(a)] It has been demonstrated that the low-molecular-weight Apo(a)
phenotype independently predicted coronary artery disease occurrence in a cohort of 440 unselected
HD patients in a prospective study over five years (Kronenberg et al 1999) It has been suggested
that the Apo(a) size and the Lp(a) plasma concentration may play a synergistic role in advanced
atherosclerosis
Because kidneys perform important hormonal functions there are also some serious
complications associated with a lack of important metabolic hormonal regulators in the course of
CKF The major problems are primarily renal anemia and renal bone disease (renal osteodystrophy)
Renal anemia
Renal anemia which is often associated with fatigue and cognitive and sexual dysfunction
has a significant impact on the quality of life of patients with CKF Anemia has also been identified
as an important etiologic factor in the development of left ventricular hypertrophy an independent
risk factor for heart failure and a predictor of mortality in HD patients (Golper et al 2003) The
major cause of renal anemia in CKF is an inadequate production of the glycoprotein hormone
erythropoietin (EPO) because of a reduction in functional kidney parenchyma (Santoro 2002)
Furthermore free radicals elicited from leucocytes by their contact with the dialysis membrane
cause hemolysis with consecutive anemia in CKF patients on extracorporeal renal replacement
therapy (Eiselt et al 1999)
There are a number of other metabolic derangements associated with uremia that can affect
the production and survival of red blood cells (eg some uremic toxins parathormone protein
malnutrition) (Golper et al 2003 Eschbach and Adamson 1985) The introduction of recombinant
human EPO (rHuEPO) has revolutionized the treatment of anemia in CKF The vast majority of
patients respond very well to treatment but 5ndash10 of patients show some resistance to rHuEPO
the most common causes of which are considered iron deficiency (Santoro 2002) and the
development of MICS (Kalantar-Zadeh et al 2003) The EPO hyporesponsiveness can further
worsen symptoms that decrease the quality of life such as an intolerance of physical work
deterioration of cognitive functions anorexia insomnia or depression These problems are partly
related to the deficit of L-carnitine in HD patients (dialysis-related carnitine disorder) This disorder
is a functional metabolic deficiency common in chronic HD patients and can have a negative impact
on erythrocyte production and survival Laboratory studies examining the influence of carnitine on
red blood cell function and clinical trials in HD patients support the use of L-carnitine in the setting
of rHuEPO hyporesponsiveness (Golper et al 2003)
Renal osteodystrophy
Renal osteodystrophy which is the term used to describe the skeletal abnormalities of many
CKD patients is a multifactorial disorder of bone remodeling It encompasses a heterogeneous
group of disorders from states of high bone turnover to states of low bone turnover High-turnover
bone disease or osteitis fibrosa represents the manifestations of secondary hyperparathyroidism
(SHPT) on bone Low bone turnover syndromes are represented by the increasingly prevalent
adynamic bone or less commonly by osteomalacia These disorders may occur in combination or
alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most
important factor which is probably responsible for SHPT development is a deficit of active vitamin
D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is
a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the
small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this
situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting
hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and
subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this
harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one
or more of them may predominate in a particular patient during the course of CKF much overlap
occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an
important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular
calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)
The treatment of vitamin D deficiency when present in CKD patients is warranted since such
therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of
20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by
supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended
daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in
stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in
dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the
serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used
to treat vitamin D deficiency (National Kidney Foundation 2004)
Cardiovascular disease
CVD is the leading cause of death in patients with CKF For every registry reporting national
dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD
(Foley et al 1998) In comparison with the general population dialysis patients have a greater than
20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these
deaths are related to vascular occlusive disease with associated myocardial infarction
cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with
CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis
and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion
to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin
The evidence suggests that the damage is already far progressed when patients reach ESRD thus
effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with
albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional
risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential
(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)
recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin
concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than
1 g of protein24 hours (National Kidney Foundation 2002)
The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL
cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)
However as mentioned above some CKD patients with the lowest cholesterol levels are the most
likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac
risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)
Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism
uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et
al 1999)
Oxidative stress
Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds
the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly
reactive substances with an unpaired electron in the outer orbital and other related reactive
compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and
nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998
Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and
consequently are not recognized by cell LDL receptors They are subsequently accumulated in the
blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of
atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications
(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of
chronic inflammation) Free radicals originate from leucocytes which are activated during the
contact with the dialysis membrane and also from erythrocyte iron released as a consequence of
hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of
EPO treatment can also contribute to oxidative stress increasing free radical production by the so-
called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of
mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions
to more dangerous Fe(II) compounds (Eiselt et al 2006)
Dialysis-related amyloidosis
Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal
replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA
Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel
syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular
pathogenesis of this complication remains unknown Recent studies however have suggested a
pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased
carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in
uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation
end-product production Thus uremia might be a state of carbonyl overload with potentially
damaging proteins (carbonyl stress) (Miyata et al 1999)
Hyperhomocysteinemia and endothelial dysfunction
Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma
concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The
causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a
result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is
considered to be an independent risk factor for the development of CVD As mentioned above
reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased
Hcy levels appear to be paradoxically associated with a better clinical outcome The development of
MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration
is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy
was inversely correlated with subjective global nutritional assessment and positively correlated with
serum albumin and protein intake Thus serum albumin concentration is a strong determinant of
plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished
patients (Suliman et al 2001)
On the other hand the toxicity of Hcy results from the structural modification of proteins and
DNA Disruption of DNA methylation has been demonstrated to occur as a result of
hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a
principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may
impair endothelial function by the generation of oxygen species and decreased NO bioavailability
Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system
in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic
et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis
endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation
(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of
the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise
mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function
in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation
of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing
connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly
by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are
elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)
In some studies an increased level of ADMA has been identified as an independent predictor of
mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function
in CRF may offer a novel strategy to reduce CVD
Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately
it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney
Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with
risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years
and family history of CKD When CKD is detected an attempt should be made to identify and treat
the underlying conditions as well as the secondary abnormalities These goals include slowing
disease progression detecting and treating complications and managing cardiovascular risk factors
Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition
anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase
balance At the same time it is necessary to continue research projects focused on other areas that
may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas
include the development of MICS management of oxidative stress and endothelium protection
Clearly progress in management of CVD in patients with CKD will require collaboration with
experts in the research and treatment of vascular disease
Conclusion
CKD leading to CKF is an urgent medical problem in the context of demographic trends In
addition to the basic kidney disease many metabolic disorders develop in the course of CKF
Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment
decreases the accumulation of metabolites however it contributes to a deficit of some important
metabolic regulators and to the development of a chronic inflammation state These factors can lead
to serious secondary complications in CKF including atherosclerosis and related cardiovascular
disease malnutrition anemia renal bone disease and other problems These complications
markedly and negatively affect the prognosis and quality of life of patients with CKF and increase
costs for their treatment The prognosis of CKD patients can be improved if kidney disease is
diagnosed early and properly cured inclusive of the secondary complications Appropriate
treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and
hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for
kidney disease and to develop new therapeutic methods to improve the quality of life of CKD
patients At the same time we must try to reduce economic costs connected with treatment
Acknowledgments
This work was supported by the research project MSM 0021620819
References
ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52
1997
ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am
J Kidney Dis 21 573-592 1993
CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal
failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005
DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33
2005
DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several
potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003
DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of
chronic kidney disease Hemodial Int 10 42-48 2006
DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic
predialysis and hemodialysis patients J Nephrol 17 813-818 2004
DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P
PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and
hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001
DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte
defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66
76-80 1994
EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on
oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in
Press
EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy
Vnitr Lek 45 319-324 1999
ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985
FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M
GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential
hypertension N Engl J Med 317 350-357 1987
FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in
chronic renal disease Am J Kidney Dis 32 S112-S119 1998
GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular
calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005
GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the
risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004
GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J
Kidney Dis 41 (4 Suppl 4) S27-S34 2003
GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193
2001
GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-
carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis
patients Contrib Nephrol 98 36-43 1992
IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity
with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study
Kidney Int 55 1945-1951 1999
IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic
dialysis patients Semin Dial 17 471-478 2004
KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-
inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis
42 864-881 2003
KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M
COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation
Curr Opin Clin Nutr Metab Care 8 388-396 2005
KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON
DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health
Perspect 1 289-295 1998
KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997
KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J
Kidney Dis 24 1002-1009 1994
KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed
patients Am J Nephrol 23 158-164 2003
KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and
treatment Am J Kidney Dis 45 978-993 2005
KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A
MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an
independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up
J Am Soc Nephrol 10 1027-1036 1999
LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D
HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney
disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney
Int 67 2089-2100 2005
LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial
Transplant 14 828-833 1999
LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving
intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
Introduction
Chronic kidney disease (CKD) is a very real and growing problem as indicated by
demographic trends The total number of treated patients has markedly increased during the last 30
years and CKD currently affects approximately 19 million adult Americans with an incidence that
is increasing rapidly (Snyder and Pendergraph 2005) This trend is caused by a growing percentage
of elderly people in the population as well as by technical progress and broader availability of
dialysis therapy An increasing number of diabetic patients is also an important factor
CKD is characterized by progressive deterioration of kidney function which develops
eventually into a terminal stage of chronic kidney failure (CKF) CKF has traditionally been
categorized as mild moderate or severe Other poorly defined terms like uremia and end-stage
renal disease (ESRD) have commonly been applied During the last few years an international
consensus has emerged categorizing CKF into 5 stages according to the glomerular filtration rate
(GFR) and presence of signs of kidney damage stage 1 GFR gt 90 mlmin and signs of kidney
damage stage 2 GFR = 60ndash89 mlmin and signs of kidney damage stage 3 GFR = 30ndash59 mlmin
stage 4 GFR = 15ndash29 mlmin and stage 5 GFR lt 15 mlmin (Levey et al 2005)
Stage 5 represents the total inability of kidneys to maintain homeostasis and this metabolic
state is incompatible with life Thus at this stage it is necessary to use methods that substitute for
kidney function to ensure patient survival these methods include peritoneal dialysis hemodialysis
and other extracorporeal purifying procedures or kidney transplantation
CKF is associated with many kinds of metabolic changes caused by the kidney disease and
also attributable to dialysis treatment Phenomena such as accumulation or deficit of various
substances and dysregulation of metabolic pathways combine in the pathogenesis of these changes
(Cibulka et al 2005) In the process of accumulation decreased urinary excretion plays a crucial
role and leads to retention of metabolites in the organism (eg creatinine urea electrolytes water)
The increased formation of metabolites through catabolic processes and alternative metabolic
pathways also wields an influence Regular dialysis treatment partly decreases this accumulation
but cannot avert the overall deficit
This deficit of some important substances in CKF can be caused by deficient intake in diet
impaired intestinal absorption or increased losses during dialysis sessions Disturbed synthesis of
some crucial metabolic regulators (eg erythropoietin active vitamin D) in kidneys also plays an
important role
All of the abovementioned factors lead to many serious complications for CKD patients
during the course of predialysis and dialysis All accelerate development of atherosclerosis
malnutrition-inflammation complex syndrome (MICS) anemia hyperparathyroidism and other
serious problems that markedly affect prognosis and the quality of life of patients with CKF
(Cibulka et al 2005 Lindner et al 1974 Durak et al 1994 Silver 2000)
Metabolic disorders in CKF
Acidndashbase balance
Acidndashbase disorder is commonly observed in the course of CKF Metabolic acidosis is noted
in a majority of patients when GFR decreases to less than 20 to 25 of normal The degree of
acidosis approximately correlates with the severity of CKF and usually is more severe at a lower
GFR Metabolic acidosis can be of the high-anion-gap variety although anion gap can be normal or
only moderately increased even with stage 4 or 5 CKF (Kraut and Kurtz 2005) In mild chronic
renal insufficiency metabolic acidosis is the result of a reduced ability to reabsorb bicarbonate to
excrete ammonia and to eliminate titratable acid excretion (hyperchloremic normal anion gap
acidosis) In more severe renal insufficiency organic and other conjugate anions of acids
(nonvolatile acids) cannot be sufficiently excreted and elevated anion gap acidosis appears
(Kovacic et al 2003) Acidosis resulting from advanced renal insufficiency is called uremic
acidosis The level of GFR at which uremic acidosis develops varies depending on a multiplicity of
factors Endogenous acid production is an important factor which in turn depends on the diet
Ingestion of vegetables and fruits results in net production of alkali and therefore increased
ingestion of these foods will tend to delay the appearance of metabolic acidosis in chronic renal
failure Diuretic therapy and hypokalemia which tend to stimulate ammonia production may delay
the development of acidosis The etiology of the renal disease also plays a role In predominantly
tubulointerstitial renal diseases acidosis tends to develop earlier in the course of renal insufficiency
than in predominantly glomerular diseases In general metabolic acidosis is rare when the GFR is
greater than 25ndash20 mlmin (Oh et al 2004)
Several adverse consequences have been associated with uremic acidosis including muscle
wasting bone disease abnormalities in growth hormone and thyroid hormone secretion impaired
insulin sensitivity and exacerbation of beta-2 microglobulin accumulation (Kraut and Kurtz 2005)
Other complications include negative nitrogen balance anorexia fatigue impaired function of the
cardiovascular system hyperkalemia and altered gluconeogenesis and triglyceride metabolism
(Kovacic et al 2003)
Therapy of uremic acidosis should aim to obtain a serum bicarbonate level as close to normal
as possible (ie 22ndash26 mmoll) The best way to initiate therapy is with oral sodium bicarbonate (1
tablet three times a day) and to increase the dosage as necessary The usual tablet of 650 mg of
sodium bicarbonate contains 75 mmol of alkali (HCO3- ions) Occasionally patients experience
gastric discomfort with sodium bicarbonate may use Shohlrsquos solution (a mixture of sodium citrate
and citric acid) In dialysis patients treatment of acidosis relies on the gain of alkali from the
dialysate either as bicarbonate in hemodialysis or as lactate in peritoneal dialysis (Oh et al 2004)
Protein metabolism
A too-strict low-protein diet can have a negative effect on nitrogen balance in the predialysis
period A safe low-protein diet should contain 06 g of proteinkgday minimally Disorders in
protein metabolism in the dialysis period are usually caused by combined (protein and energy)
malnutrition that can be termed uremic malnutrition It is present in approximately 20ndash50 of
patients on dialysis and is characterized by insidious loss of somatic protein stores (reflected in lean
body mass and serum creatinine) and visceral protein concentrations (reflected in serum albumin
and prealbumin concentrations) (Ikizler 2004) Urinary losses of protein and losses of amino acids
during a dialysis session may play a role as well Metabolic acidosis is an important factor that
markedly contributes to negative nitrogen and total body protein balance in CKF (Kovacic et al
2003 Mehrotra et al 2003) It has been demonstrated that the presence of uremic malnutrition
increases mortality and morbidity in chronic dialysis patients (Kopple 1994 Ikizler et al 1999) It
is very often combined with a chronic inflammation state in the syndrome known as MICS
(Kalantar-Zadeh et al 2003)
Carbohydrate metabolism
Disorders of carbohydrate metabolism are also very frequent in CKD Diabetics represent
about 35 of all patients on dialysis therapy Generally non-diabetic CKD patients often also have
glucose intolerance probably because of peripheral insulin resistance (Alvestrand 1997) Insulin
resistance is primarily detectable when the GFR is below 50 mlmin Reduced insulin-mediated
non-oxidative glucose disposal is the most evident defect of glucose metabolism but impairments
of glucose oxidation the defective suppression of endogenous glucose production and abnormal
insulin secretion also contribute to uremic glucose intolerance (Rigalleau and Gin 2005)
Accumulating nitrogenous uremic toxins seem to be the dominant cause of a specific defect in
insulin action and identification of these toxins is progressing particularly in the field of
carbamoylated amino acids The consequences of CKF such as exercise intolerance anemia
metabolic acidosis secondary hyperparathyroidism or vitamin D deficiency also indirectly play a
role (Rigalleau and Gin 2005 Rasic-Milutinovic et al 2000) It has been reported that insulin
resistance may be related to arterial hypertension (Ferrannini et al 1987) and may contribute to
high cardiovascular morbidity and mortality in patients with CKF (Shoji et al 2001 Shinohara et
al 2002) The underlying mechanism can be an impaired synthesis of nitric oxide (NO) in
endothelium of patients with CKD It was reported that appropriately functioning endothelial NO
synthase (eNOS) is important for the control not only of arterial pressure but also of glucose and
lipid homeostasis (Duplain et al 2001)
Lipid metabolism
Serum triglycerides (TG) are elevated in CKF because of enhanced production of TG-rich
lipoproteins such as very-low-density lipoproteins (VLDL) in the liver (Attman et al 1993) and
also because of dysfunction of TG degradation resulting from insufficient mitochondrial beta-
oxidation of fatty acids It can be caused by a deficit of L-carnitine which is frequently present
especially in hemodialysis (HD) patients (Cibulka et al 2005 Guarnieri et al 1992)
Hyperinsulinemia is the main factor increasing synthesis of TG and also directly decreases activity
of lipoprotein lipase The following changes in lipid metabolism are also found in many patients
with CKF The most prominent are increased serum TG levels and low levels of high-density
lipoprotein (HDL) cholesterol Low-density lipoprotein (LDL) cholesterol levels are often normal
but the cholesterol may originate from the atherogenic small and dense LDL subclass The
apolipoprotein B-containing part of the lipoprotein may undergo modifications (peptide
modification of the enzymatic and advanced glycation end-product oxidation or glycation)
Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote
prolonged circulation HDL particles are structurally altered during states of inflammation The
contribution of this complex and the atherogenic form of dyslipidemia to cardiovascular disease
(CVD) in patients with renal disease is at present unclear
Some studies report negative results regarding the predictive power of serum lipids for the
development of CVD (Wanner and Krane 2002) Recent findings have suggested that the
development of MICS is responsible for this phenomenon Because MICS leads to a low body mass
index hypocholesterolemia hypocreatininemia hypohomocysteinemia and other manifestations a
reverse epidemiology of traditional cardiovascular risk factors occurs in CKF Therefore
hypercholesterolemia obesity and increased blood levels of creatinine and homocysteine appear to
be protective and paradoxically associated with a better outcome in patients with CKF (Kalantar-
Zadeh et al 2003 Kalantar-Zadeh et al 2005)
It is well known that HDL cholesterol levels are inversely correlated with the risk of
atherosclerosis In addition to its role in reverse cholesterol transport HDL has the ability to protect
LDL particles against oxidation The underlying mechanism by which HDL inhibits LDL oxidation
is partly enzymatic There is increasing evidence that paraoxonase 1 (PON1) could be involved in
this process (Mackness et al 1993) It was proved that serum PON1 activity is reduced in CKF
patients The possible causes can include reduced HDL levels altered HDL subfraction distribution
reduced PON1 concentration and different PON1 phenotype distributions Another possible
explanation could be that PON1 activity is inhibited in the uremic environment Generally reduced
serum PON1 activity could also contribute to the accelerated development of atherosclerosis in
CKF patients (Dirican et al 2004)
Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for atherosclerotic
CVD It was found to be consistently elevated in a considerable proportion of CKD patients Plasma
concentrations of Lp(a) are highly heritable and mainly determined by a size polymorphism of
apolipoprotein(a) [Apo(a)] It has been demonstrated that the low-molecular-weight Apo(a)
phenotype independently predicted coronary artery disease occurrence in a cohort of 440 unselected
HD patients in a prospective study over five years (Kronenberg et al 1999) It has been suggested
that the Apo(a) size and the Lp(a) plasma concentration may play a synergistic role in advanced
atherosclerosis
Because kidneys perform important hormonal functions there are also some serious
complications associated with a lack of important metabolic hormonal regulators in the course of
CKF The major problems are primarily renal anemia and renal bone disease (renal osteodystrophy)
Renal anemia
Renal anemia which is often associated with fatigue and cognitive and sexual dysfunction
has a significant impact on the quality of life of patients with CKF Anemia has also been identified
as an important etiologic factor in the development of left ventricular hypertrophy an independent
risk factor for heart failure and a predictor of mortality in HD patients (Golper et al 2003) The
major cause of renal anemia in CKF is an inadequate production of the glycoprotein hormone
erythropoietin (EPO) because of a reduction in functional kidney parenchyma (Santoro 2002)
Furthermore free radicals elicited from leucocytes by their contact with the dialysis membrane
cause hemolysis with consecutive anemia in CKF patients on extracorporeal renal replacement
therapy (Eiselt et al 1999)
There are a number of other metabolic derangements associated with uremia that can affect
the production and survival of red blood cells (eg some uremic toxins parathormone protein
malnutrition) (Golper et al 2003 Eschbach and Adamson 1985) The introduction of recombinant
human EPO (rHuEPO) has revolutionized the treatment of anemia in CKF The vast majority of
patients respond very well to treatment but 5ndash10 of patients show some resistance to rHuEPO
the most common causes of which are considered iron deficiency (Santoro 2002) and the
development of MICS (Kalantar-Zadeh et al 2003) The EPO hyporesponsiveness can further
worsen symptoms that decrease the quality of life such as an intolerance of physical work
deterioration of cognitive functions anorexia insomnia or depression These problems are partly
related to the deficit of L-carnitine in HD patients (dialysis-related carnitine disorder) This disorder
is a functional metabolic deficiency common in chronic HD patients and can have a negative impact
on erythrocyte production and survival Laboratory studies examining the influence of carnitine on
red blood cell function and clinical trials in HD patients support the use of L-carnitine in the setting
of rHuEPO hyporesponsiveness (Golper et al 2003)
Renal osteodystrophy
Renal osteodystrophy which is the term used to describe the skeletal abnormalities of many
CKD patients is a multifactorial disorder of bone remodeling It encompasses a heterogeneous
group of disorders from states of high bone turnover to states of low bone turnover High-turnover
bone disease or osteitis fibrosa represents the manifestations of secondary hyperparathyroidism
(SHPT) on bone Low bone turnover syndromes are represented by the increasingly prevalent
adynamic bone or less commonly by osteomalacia These disorders may occur in combination or
alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most
important factor which is probably responsible for SHPT development is a deficit of active vitamin
D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is
a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the
small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this
situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting
hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and
subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this
harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one
or more of them may predominate in a particular patient during the course of CKF much overlap
occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an
important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular
calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)
The treatment of vitamin D deficiency when present in CKD patients is warranted since such
therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of
20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by
supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended
daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in
stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in
dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the
serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used
to treat vitamin D deficiency (National Kidney Foundation 2004)
Cardiovascular disease
CVD is the leading cause of death in patients with CKF For every registry reporting national
dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD
(Foley et al 1998) In comparison with the general population dialysis patients have a greater than
20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these
deaths are related to vascular occlusive disease with associated myocardial infarction
cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with
CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis
and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion
to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin
The evidence suggests that the damage is already far progressed when patients reach ESRD thus
effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with
albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional
risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential
(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)
recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin
concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than
1 g of protein24 hours (National Kidney Foundation 2002)
The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL
cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)
However as mentioned above some CKD patients with the lowest cholesterol levels are the most
likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac
risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)
Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism
uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et
al 1999)
Oxidative stress
Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds
the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly
reactive substances with an unpaired electron in the outer orbital and other related reactive
compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and
nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998
Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and
consequently are not recognized by cell LDL receptors They are subsequently accumulated in the
blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of
atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications
(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of
chronic inflammation) Free radicals originate from leucocytes which are activated during the
contact with the dialysis membrane and also from erythrocyte iron released as a consequence of
hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of
EPO treatment can also contribute to oxidative stress increasing free radical production by the so-
called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of
mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions
to more dangerous Fe(II) compounds (Eiselt et al 2006)
Dialysis-related amyloidosis
Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal
replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA
Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel
syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular
pathogenesis of this complication remains unknown Recent studies however have suggested a
pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased
carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in
uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation
end-product production Thus uremia might be a state of carbonyl overload with potentially
damaging proteins (carbonyl stress) (Miyata et al 1999)
Hyperhomocysteinemia and endothelial dysfunction
Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma
concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The
causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a
result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is
considered to be an independent risk factor for the development of CVD As mentioned above
reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased
Hcy levels appear to be paradoxically associated with a better clinical outcome The development of
MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration
is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy
was inversely correlated with subjective global nutritional assessment and positively correlated with
serum albumin and protein intake Thus serum albumin concentration is a strong determinant of
plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished
patients (Suliman et al 2001)
On the other hand the toxicity of Hcy results from the structural modification of proteins and
DNA Disruption of DNA methylation has been demonstrated to occur as a result of
hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a
principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may
impair endothelial function by the generation of oxygen species and decreased NO bioavailability
Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system
in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic
et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis
endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation
(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of
the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise
mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function
in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation
of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing
connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly
by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are
elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)
In some studies an increased level of ADMA has been identified as an independent predictor of
mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function
in CRF may offer a novel strategy to reduce CVD
Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately
it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney
Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with
risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years
and family history of CKD When CKD is detected an attempt should be made to identify and treat
the underlying conditions as well as the secondary abnormalities These goals include slowing
disease progression detecting and treating complications and managing cardiovascular risk factors
Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition
anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase
balance At the same time it is necessary to continue research projects focused on other areas that
may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas
include the development of MICS management of oxidative stress and endothelium protection
Clearly progress in management of CVD in patients with CKD will require collaboration with
experts in the research and treatment of vascular disease
Conclusion
CKD leading to CKF is an urgent medical problem in the context of demographic trends In
addition to the basic kidney disease many metabolic disorders develop in the course of CKF
Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment
decreases the accumulation of metabolites however it contributes to a deficit of some important
metabolic regulators and to the development of a chronic inflammation state These factors can lead
to serious secondary complications in CKF including atherosclerosis and related cardiovascular
disease malnutrition anemia renal bone disease and other problems These complications
markedly and negatively affect the prognosis and quality of life of patients with CKF and increase
costs for their treatment The prognosis of CKD patients can be improved if kidney disease is
diagnosed early and properly cured inclusive of the secondary complications Appropriate
treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and
hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for
kidney disease and to develop new therapeutic methods to improve the quality of life of CKD
patients At the same time we must try to reduce economic costs connected with treatment
Acknowledgments
This work was supported by the research project MSM 0021620819
References
ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52
1997
ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am
J Kidney Dis 21 573-592 1993
CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal
failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005
DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33
2005
DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several
potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003
DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of
chronic kidney disease Hemodial Int 10 42-48 2006
DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic
predialysis and hemodialysis patients J Nephrol 17 813-818 2004
DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P
PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and
hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001
DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte
defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66
76-80 1994
EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on
oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in
Press
EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy
Vnitr Lek 45 319-324 1999
ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985
FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M
GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential
hypertension N Engl J Med 317 350-357 1987
FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in
chronic renal disease Am J Kidney Dis 32 S112-S119 1998
GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular
calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005
GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the
risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004
GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J
Kidney Dis 41 (4 Suppl 4) S27-S34 2003
GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193
2001
GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-
carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis
patients Contrib Nephrol 98 36-43 1992
IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity
with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study
Kidney Int 55 1945-1951 1999
IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic
dialysis patients Semin Dial 17 471-478 2004
KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-
inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis
42 864-881 2003
KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M
COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation
Curr Opin Clin Nutr Metab Care 8 388-396 2005
KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON
DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health
Perspect 1 289-295 1998
KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997
KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J
Kidney Dis 24 1002-1009 1994
KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed
patients Am J Nephrol 23 158-164 2003
KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and
treatment Am J Kidney Dis 45 978-993 2005
KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A
MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an
independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up
J Am Soc Nephrol 10 1027-1036 1999
LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D
HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney
disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney
Int 67 2089-2100 2005
LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial
Transplant 14 828-833 1999
LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving
intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
pathways also wields an influence Regular dialysis treatment partly decreases this accumulation
but cannot avert the overall deficit
This deficit of some important substances in CKF can be caused by deficient intake in diet
impaired intestinal absorption or increased losses during dialysis sessions Disturbed synthesis of
some crucial metabolic regulators (eg erythropoietin active vitamin D) in kidneys also plays an
important role
All of the abovementioned factors lead to many serious complications for CKD patients
during the course of predialysis and dialysis All accelerate development of atherosclerosis
malnutrition-inflammation complex syndrome (MICS) anemia hyperparathyroidism and other
serious problems that markedly affect prognosis and the quality of life of patients with CKF
(Cibulka et al 2005 Lindner et al 1974 Durak et al 1994 Silver 2000)
Metabolic disorders in CKF
Acidndashbase balance
Acidndashbase disorder is commonly observed in the course of CKF Metabolic acidosis is noted
in a majority of patients when GFR decreases to less than 20 to 25 of normal The degree of
acidosis approximately correlates with the severity of CKF and usually is more severe at a lower
GFR Metabolic acidosis can be of the high-anion-gap variety although anion gap can be normal or
only moderately increased even with stage 4 or 5 CKF (Kraut and Kurtz 2005) In mild chronic
renal insufficiency metabolic acidosis is the result of a reduced ability to reabsorb bicarbonate to
excrete ammonia and to eliminate titratable acid excretion (hyperchloremic normal anion gap
acidosis) In more severe renal insufficiency organic and other conjugate anions of acids
(nonvolatile acids) cannot be sufficiently excreted and elevated anion gap acidosis appears
(Kovacic et al 2003) Acidosis resulting from advanced renal insufficiency is called uremic
acidosis The level of GFR at which uremic acidosis develops varies depending on a multiplicity of
factors Endogenous acid production is an important factor which in turn depends on the diet
Ingestion of vegetables and fruits results in net production of alkali and therefore increased
ingestion of these foods will tend to delay the appearance of metabolic acidosis in chronic renal
failure Diuretic therapy and hypokalemia which tend to stimulate ammonia production may delay
the development of acidosis The etiology of the renal disease also plays a role In predominantly
tubulointerstitial renal diseases acidosis tends to develop earlier in the course of renal insufficiency
than in predominantly glomerular diseases In general metabolic acidosis is rare when the GFR is
greater than 25ndash20 mlmin (Oh et al 2004)
Several adverse consequences have been associated with uremic acidosis including muscle
wasting bone disease abnormalities in growth hormone and thyroid hormone secretion impaired
insulin sensitivity and exacerbation of beta-2 microglobulin accumulation (Kraut and Kurtz 2005)
Other complications include negative nitrogen balance anorexia fatigue impaired function of the
cardiovascular system hyperkalemia and altered gluconeogenesis and triglyceride metabolism
(Kovacic et al 2003)
Therapy of uremic acidosis should aim to obtain a serum bicarbonate level as close to normal
as possible (ie 22ndash26 mmoll) The best way to initiate therapy is with oral sodium bicarbonate (1
tablet three times a day) and to increase the dosage as necessary The usual tablet of 650 mg of
sodium bicarbonate contains 75 mmol of alkali (HCO3- ions) Occasionally patients experience
gastric discomfort with sodium bicarbonate may use Shohlrsquos solution (a mixture of sodium citrate
and citric acid) In dialysis patients treatment of acidosis relies on the gain of alkali from the
dialysate either as bicarbonate in hemodialysis or as lactate in peritoneal dialysis (Oh et al 2004)
Protein metabolism
A too-strict low-protein diet can have a negative effect on nitrogen balance in the predialysis
period A safe low-protein diet should contain 06 g of proteinkgday minimally Disorders in
protein metabolism in the dialysis period are usually caused by combined (protein and energy)
malnutrition that can be termed uremic malnutrition It is present in approximately 20ndash50 of
patients on dialysis and is characterized by insidious loss of somatic protein stores (reflected in lean
body mass and serum creatinine) and visceral protein concentrations (reflected in serum albumin
and prealbumin concentrations) (Ikizler 2004) Urinary losses of protein and losses of amino acids
during a dialysis session may play a role as well Metabolic acidosis is an important factor that
markedly contributes to negative nitrogen and total body protein balance in CKF (Kovacic et al
2003 Mehrotra et al 2003) It has been demonstrated that the presence of uremic malnutrition
increases mortality and morbidity in chronic dialysis patients (Kopple 1994 Ikizler et al 1999) It
is very often combined with a chronic inflammation state in the syndrome known as MICS
(Kalantar-Zadeh et al 2003)
Carbohydrate metabolism
Disorders of carbohydrate metabolism are also very frequent in CKD Diabetics represent
about 35 of all patients on dialysis therapy Generally non-diabetic CKD patients often also have
glucose intolerance probably because of peripheral insulin resistance (Alvestrand 1997) Insulin
resistance is primarily detectable when the GFR is below 50 mlmin Reduced insulin-mediated
non-oxidative glucose disposal is the most evident defect of glucose metabolism but impairments
of glucose oxidation the defective suppression of endogenous glucose production and abnormal
insulin secretion also contribute to uremic glucose intolerance (Rigalleau and Gin 2005)
Accumulating nitrogenous uremic toxins seem to be the dominant cause of a specific defect in
insulin action and identification of these toxins is progressing particularly in the field of
carbamoylated amino acids The consequences of CKF such as exercise intolerance anemia
metabolic acidosis secondary hyperparathyroidism or vitamin D deficiency also indirectly play a
role (Rigalleau and Gin 2005 Rasic-Milutinovic et al 2000) It has been reported that insulin
resistance may be related to arterial hypertension (Ferrannini et al 1987) and may contribute to
high cardiovascular morbidity and mortality in patients with CKF (Shoji et al 2001 Shinohara et
al 2002) The underlying mechanism can be an impaired synthesis of nitric oxide (NO) in
endothelium of patients with CKD It was reported that appropriately functioning endothelial NO
synthase (eNOS) is important for the control not only of arterial pressure but also of glucose and
lipid homeostasis (Duplain et al 2001)
Lipid metabolism
Serum triglycerides (TG) are elevated in CKF because of enhanced production of TG-rich
lipoproteins such as very-low-density lipoproteins (VLDL) in the liver (Attman et al 1993) and
also because of dysfunction of TG degradation resulting from insufficient mitochondrial beta-
oxidation of fatty acids It can be caused by a deficit of L-carnitine which is frequently present
especially in hemodialysis (HD) patients (Cibulka et al 2005 Guarnieri et al 1992)
Hyperinsulinemia is the main factor increasing synthesis of TG and also directly decreases activity
of lipoprotein lipase The following changes in lipid metabolism are also found in many patients
with CKF The most prominent are increased serum TG levels and low levels of high-density
lipoprotein (HDL) cholesterol Low-density lipoprotein (LDL) cholesterol levels are often normal
but the cholesterol may originate from the atherogenic small and dense LDL subclass The
apolipoprotein B-containing part of the lipoprotein may undergo modifications (peptide
modification of the enzymatic and advanced glycation end-product oxidation or glycation)
Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote
prolonged circulation HDL particles are structurally altered during states of inflammation The
contribution of this complex and the atherogenic form of dyslipidemia to cardiovascular disease
(CVD) in patients with renal disease is at present unclear
Some studies report negative results regarding the predictive power of serum lipids for the
development of CVD (Wanner and Krane 2002) Recent findings have suggested that the
development of MICS is responsible for this phenomenon Because MICS leads to a low body mass
index hypocholesterolemia hypocreatininemia hypohomocysteinemia and other manifestations a
reverse epidemiology of traditional cardiovascular risk factors occurs in CKF Therefore
hypercholesterolemia obesity and increased blood levels of creatinine and homocysteine appear to
be protective and paradoxically associated with a better outcome in patients with CKF (Kalantar-
Zadeh et al 2003 Kalantar-Zadeh et al 2005)
It is well known that HDL cholesterol levels are inversely correlated with the risk of
atherosclerosis In addition to its role in reverse cholesterol transport HDL has the ability to protect
LDL particles against oxidation The underlying mechanism by which HDL inhibits LDL oxidation
is partly enzymatic There is increasing evidence that paraoxonase 1 (PON1) could be involved in
this process (Mackness et al 1993) It was proved that serum PON1 activity is reduced in CKF
patients The possible causes can include reduced HDL levels altered HDL subfraction distribution
reduced PON1 concentration and different PON1 phenotype distributions Another possible
explanation could be that PON1 activity is inhibited in the uremic environment Generally reduced
serum PON1 activity could also contribute to the accelerated development of atherosclerosis in
CKF patients (Dirican et al 2004)
Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for atherosclerotic
CVD It was found to be consistently elevated in a considerable proportion of CKD patients Plasma
concentrations of Lp(a) are highly heritable and mainly determined by a size polymorphism of
apolipoprotein(a) [Apo(a)] It has been demonstrated that the low-molecular-weight Apo(a)
phenotype independently predicted coronary artery disease occurrence in a cohort of 440 unselected
HD patients in a prospective study over five years (Kronenberg et al 1999) It has been suggested
that the Apo(a) size and the Lp(a) plasma concentration may play a synergistic role in advanced
atherosclerosis
Because kidneys perform important hormonal functions there are also some serious
complications associated with a lack of important metabolic hormonal regulators in the course of
CKF The major problems are primarily renal anemia and renal bone disease (renal osteodystrophy)
Renal anemia
Renal anemia which is often associated with fatigue and cognitive and sexual dysfunction
has a significant impact on the quality of life of patients with CKF Anemia has also been identified
as an important etiologic factor in the development of left ventricular hypertrophy an independent
risk factor for heart failure and a predictor of mortality in HD patients (Golper et al 2003) The
major cause of renal anemia in CKF is an inadequate production of the glycoprotein hormone
erythropoietin (EPO) because of a reduction in functional kidney parenchyma (Santoro 2002)
Furthermore free radicals elicited from leucocytes by their contact with the dialysis membrane
cause hemolysis with consecutive anemia in CKF patients on extracorporeal renal replacement
therapy (Eiselt et al 1999)
There are a number of other metabolic derangements associated with uremia that can affect
the production and survival of red blood cells (eg some uremic toxins parathormone protein
malnutrition) (Golper et al 2003 Eschbach and Adamson 1985) The introduction of recombinant
human EPO (rHuEPO) has revolutionized the treatment of anemia in CKF The vast majority of
patients respond very well to treatment but 5ndash10 of patients show some resistance to rHuEPO
the most common causes of which are considered iron deficiency (Santoro 2002) and the
development of MICS (Kalantar-Zadeh et al 2003) The EPO hyporesponsiveness can further
worsen symptoms that decrease the quality of life such as an intolerance of physical work
deterioration of cognitive functions anorexia insomnia or depression These problems are partly
related to the deficit of L-carnitine in HD patients (dialysis-related carnitine disorder) This disorder
is a functional metabolic deficiency common in chronic HD patients and can have a negative impact
on erythrocyte production and survival Laboratory studies examining the influence of carnitine on
red blood cell function and clinical trials in HD patients support the use of L-carnitine in the setting
of rHuEPO hyporesponsiveness (Golper et al 2003)
Renal osteodystrophy
Renal osteodystrophy which is the term used to describe the skeletal abnormalities of many
CKD patients is a multifactorial disorder of bone remodeling It encompasses a heterogeneous
group of disorders from states of high bone turnover to states of low bone turnover High-turnover
bone disease or osteitis fibrosa represents the manifestations of secondary hyperparathyroidism
(SHPT) on bone Low bone turnover syndromes are represented by the increasingly prevalent
adynamic bone or less commonly by osteomalacia These disorders may occur in combination or
alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most
important factor which is probably responsible for SHPT development is a deficit of active vitamin
D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is
a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the
small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this
situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting
hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and
subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this
harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one
or more of them may predominate in a particular patient during the course of CKF much overlap
occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an
important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular
calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)
The treatment of vitamin D deficiency when present in CKD patients is warranted since such
therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of
20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by
supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended
daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in
stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in
dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the
serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used
to treat vitamin D deficiency (National Kidney Foundation 2004)
Cardiovascular disease
CVD is the leading cause of death in patients with CKF For every registry reporting national
dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD
(Foley et al 1998) In comparison with the general population dialysis patients have a greater than
20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these
deaths are related to vascular occlusive disease with associated myocardial infarction
cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with
CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis
and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion
to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin
The evidence suggests that the damage is already far progressed when patients reach ESRD thus
effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with
albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional
risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential
(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)
recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin
concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than
1 g of protein24 hours (National Kidney Foundation 2002)
The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL
cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)
However as mentioned above some CKD patients with the lowest cholesterol levels are the most
likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac
risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)
Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism
uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et
al 1999)
Oxidative stress
Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds
the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly
reactive substances with an unpaired electron in the outer orbital and other related reactive
compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and
nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998
Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and
consequently are not recognized by cell LDL receptors They are subsequently accumulated in the
blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of
atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications
(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of
chronic inflammation) Free radicals originate from leucocytes which are activated during the
contact with the dialysis membrane and also from erythrocyte iron released as a consequence of
hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of
EPO treatment can also contribute to oxidative stress increasing free radical production by the so-
called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of
mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions
to more dangerous Fe(II) compounds (Eiselt et al 2006)
Dialysis-related amyloidosis
Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal
replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA
Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel
syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular
pathogenesis of this complication remains unknown Recent studies however have suggested a
pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased
carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in
uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation
end-product production Thus uremia might be a state of carbonyl overload with potentially
damaging proteins (carbonyl stress) (Miyata et al 1999)
Hyperhomocysteinemia and endothelial dysfunction
Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma
concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The
causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a
result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is
considered to be an independent risk factor for the development of CVD As mentioned above
reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased
Hcy levels appear to be paradoxically associated with a better clinical outcome The development of
MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration
is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy
was inversely correlated with subjective global nutritional assessment and positively correlated with
serum albumin and protein intake Thus serum albumin concentration is a strong determinant of
plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished
patients (Suliman et al 2001)
On the other hand the toxicity of Hcy results from the structural modification of proteins and
DNA Disruption of DNA methylation has been demonstrated to occur as a result of
hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a
principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may
impair endothelial function by the generation of oxygen species and decreased NO bioavailability
Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system
in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic
et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis
endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation
(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of
the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise
mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function
in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation
of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing
connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly
by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are
elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)
In some studies an increased level of ADMA has been identified as an independent predictor of
mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function
in CRF may offer a novel strategy to reduce CVD
Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately
it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney
Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with
risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years
and family history of CKD When CKD is detected an attempt should be made to identify and treat
the underlying conditions as well as the secondary abnormalities These goals include slowing
disease progression detecting and treating complications and managing cardiovascular risk factors
Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition
anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase
balance At the same time it is necessary to continue research projects focused on other areas that
may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas
include the development of MICS management of oxidative stress and endothelium protection
Clearly progress in management of CVD in patients with CKD will require collaboration with
experts in the research and treatment of vascular disease
Conclusion
CKD leading to CKF is an urgent medical problem in the context of demographic trends In
addition to the basic kidney disease many metabolic disorders develop in the course of CKF
Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment
decreases the accumulation of metabolites however it contributes to a deficit of some important
metabolic regulators and to the development of a chronic inflammation state These factors can lead
to serious secondary complications in CKF including atherosclerosis and related cardiovascular
disease malnutrition anemia renal bone disease and other problems These complications
markedly and negatively affect the prognosis and quality of life of patients with CKF and increase
costs for their treatment The prognosis of CKD patients can be improved if kidney disease is
diagnosed early and properly cured inclusive of the secondary complications Appropriate
treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and
hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for
kidney disease and to develop new therapeutic methods to improve the quality of life of CKD
patients At the same time we must try to reduce economic costs connected with treatment
Acknowledgments
This work was supported by the research project MSM 0021620819
References
ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52
1997
ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am
J Kidney Dis 21 573-592 1993
CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal
failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005
DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33
2005
DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several
potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003
DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of
chronic kidney disease Hemodial Int 10 42-48 2006
DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic
predialysis and hemodialysis patients J Nephrol 17 813-818 2004
DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P
PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and
hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001
DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte
defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66
76-80 1994
EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on
oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in
Press
EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy
Vnitr Lek 45 319-324 1999
ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985
FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M
GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential
hypertension N Engl J Med 317 350-357 1987
FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in
chronic renal disease Am J Kidney Dis 32 S112-S119 1998
GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular
calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005
GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the
risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004
GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J
Kidney Dis 41 (4 Suppl 4) S27-S34 2003
GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193
2001
GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-
carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis
patients Contrib Nephrol 98 36-43 1992
IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity
with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study
Kidney Int 55 1945-1951 1999
IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic
dialysis patients Semin Dial 17 471-478 2004
KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-
inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis
42 864-881 2003
KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M
COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation
Curr Opin Clin Nutr Metab Care 8 388-396 2005
KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON
DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health
Perspect 1 289-295 1998
KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997
KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J
Kidney Dis 24 1002-1009 1994
KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed
patients Am J Nephrol 23 158-164 2003
KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and
treatment Am J Kidney Dis 45 978-993 2005
KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A
MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an
independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up
J Am Soc Nephrol 10 1027-1036 1999
LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D
HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney
disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney
Int 67 2089-2100 2005
LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial
Transplant 14 828-833 1999
LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving
intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
ingestion of these foods will tend to delay the appearance of metabolic acidosis in chronic renal
failure Diuretic therapy and hypokalemia which tend to stimulate ammonia production may delay
the development of acidosis The etiology of the renal disease also plays a role In predominantly
tubulointerstitial renal diseases acidosis tends to develop earlier in the course of renal insufficiency
than in predominantly glomerular diseases In general metabolic acidosis is rare when the GFR is
greater than 25ndash20 mlmin (Oh et al 2004)
Several adverse consequences have been associated with uremic acidosis including muscle
wasting bone disease abnormalities in growth hormone and thyroid hormone secretion impaired
insulin sensitivity and exacerbation of beta-2 microglobulin accumulation (Kraut and Kurtz 2005)
Other complications include negative nitrogen balance anorexia fatigue impaired function of the
cardiovascular system hyperkalemia and altered gluconeogenesis and triglyceride metabolism
(Kovacic et al 2003)
Therapy of uremic acidosis should aim to obtain a serum bicarbonate level as close to normal
as possible (ie 22ndash26 mmoll) The best way to initiate therapy is with oral sodium bicarbonate (1
tablet three times a day) and to increase the dosage as necessary The usual tablet of 650 mg of
sodium bicarbonate contains 75 mmol of alkali (HCO3- ions) Occasionally patients experience
gastric discomfort with sodium bicarbonate may use Shohlrsquos solution (a mixture of sodium citrate
and citric acid) In dialysis patients treatment of acidosis relies on the gain of alkali from the
dialysate either as bicarbonate in hemodialysis or as lactate in peritoneal dialysis (Oh et al 2004)
Protein metabolism
A too-strict low-protein diet can have a negative effect on nitrogen balance in the predialysis
period A safe low-protein diet should contain 06 g of proteinkgday minimally Disorders in
protein metabolism in the dialysis period are usually caused by combined (protein and energy)
malnutrition that can be termed uremic malnutrition It is present in approximately 20ndash50 of
patients on dialysis and is characterized by insidious loss of somatic protein stores (reflected in lean
body mass and serum creatinine) and visceral protein concentrations (reflected in serum albumin
and prealbumin concentrations) (Ikizler 2004) Urinary losses of protein and losses of amino acids
during a dialysis session may play a role as well Metabolic acidosis is an important factor that
markedly contributes to negative nitrogen and total body protein balance in CKF (Kovacic et al
2003 Mehrotra et al 2003) It has been demonstrated that the presence of uremic malnutrition
increases mortality and morbidity in chronic dialysis patients (Kopple 1994 Ikizler et al 1999) It
is very often combined with a chronic inflammation state in the syndrome known as MICS
(Kalantar-Zadeh et al 2003)
Carbohydrate metabolism
Disorders of carbohydrate metabolism are also very frequent in CKD Diabetics represent
about 35 of all patients on dialysis therapy Generally non-diabetic CKD patients often also have
glucose intolerance probably because of peripheral insulin resistance (Alvestrand 1997) Insulin
resistance is primarily detectable when the GFR is below 50 mlmin Reduced insulin-mediated
non-oxidative glucose disposal is the most evident defect of glucose metabolism but impairments
of glucose oxidation the defective suppression of endogenous glucose production and abnormal
insulin secretion also contribute to uremic glucose intolerance (Rigalleau and Gin 2005)
Accumulating nitrogenous uremic toxins seem to be the dominant cause of a specific defect in
insulin action and identification of these toxins is progressing particularly in the field of
carbamoylated amino acids The consequences of CKF such as exercise intolerance anemia
metabolic acidosis secondary hyperparathyroidism or vitamin D deficiency also indirectly play a
role (Rigalleau and Gin 2005 Rasic-Milutinovic et al 2000) It has been reported that insulin
resistance may be related to arterial hypertension (Ferrannini et al 1987) and may contribute to
high cardiovascular morbidity and mortality in patients with CKF (Shoji et al 2001 Shinohara et
al 2002) The underlying mechanism can be an impaired synthesis of nitric oxide (NO) in
endothelium of patients with CKD It was reported that appropriately functioning endothelial NO
synthase (eNOS) is important for the control not only of arterial pressure but also of glucose and
lipid homeostasis (Duplain et al 2001)
Lipid metabolism
Serum triglycerides (TG) are elevated in CKF because of enhanced production of TG-rich
lipoproteins such as very-low-density lipoproteins (VLDL) in the liver (Attman et al 1993) and
also because of dysfunction of TG degradation resulting from insufficient mitochondrial beta-
oxidation of fatty acids It can be caused by a deficit of L-carnitine which is frequently present
especially in hemodialysis (HD) patients (Cibulka et al 2005 Guarnieri et al 1992)
Hyperinsulinemia is the main factor increasing synthesis of TG and also directly decreases activity
of lipoprotein lipase The following changes in lipid metabolism are also found in many patients
with CKF The most prominent are increased serum TG levels and low levels of high-density
lipoprotein (HDL) cholesterol Low-density lipoprotein (LDL) cholesterol levels are often normal
but the cholesterol may originate from the atherogenic small and dense LDL subclass The
apolipoprotein B-containing part of the lipoprotein may undergo modifications (peptide
modification of the enzymatic and advanced glycation end-product oxidation or glycation)
Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote
prolonged circulation HDL particles are structurally altered during states of inflammation The
contribution of this complex and the atherogenic form of dyslipidemia to cardiovascular disease
(CVD) in patients with renal disease is at present unclear
Some studies report negative results regarding the predictive power of serum lipids for the
development of CVD (Wanner and Krane 2002) Recent findings have suggested that the
development of MICS is responsible for this phenomenon Because MICS leads to a low body mass
index hypocholesterolemia hypocreatininemia hypohomocysteinemia and other manifestations a
reverse epidemiology of traditional cardiovascular risk factors occurs in CKF Therefore
hypercholesterolemia obesity and increased blood levels of creatinine and homocysteine appear to
be protective and paradoxically associated with a better outcome in patients with CKF (Kalantar-
Zadeh et al 2003 Kalantar-Zadeh et al 2005)
It is well known that HDL cholesterol levels are inversely correlated with the risk of
atherosclerosis In addition to its role in reverse cholesterol transport HDL has the ability to protect
LDL particles against oxidation The underlying mechanism by which HDL inhibits LDL oxidation
is partly enzymatic There is increasing evidence that paraoxonase 1 (PON1) could be involved in
this process (Mackness et al 1993) It was proved that serum PON1 activity is reduced in CKF
patients The possible causes can include reduced HDL levels altered HDL subfraction distribution
reduced PON1 concentration and different PON1 phenotype distributions Another possible
explanation could be that PON1 activity is inhibited in the uremic environment Generally reduced
serum PON1 activity could also contribute to the accelerated development of atherosclerosis in
CKF patients (Dirican et al 2004)
Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for atherosclerotic
CVD It was found to be consistently elevated in a considerable proportion of CKD patients Plasma
concentrations of Lp(a) are highly heritable and mainly determined by a size polymorphism of
apolipoprotein(a) [Apo(a)] It has been demonstrated that the low-molecular-weight Apo(a)
phenotype independently predicted coronary artery disease occurrence in a cohort of 440 unselected
HD patients in a prospective study over five years (Kronenberg et al 1999) It has been suggested
that the Apo(a) size and the Lp(a) plasma concentration may play a synergistic role in advanced
atherosclerosis
Because kidneys perform important hormonal functions there are also some serious
complications associated with a lack of important metabolic hormonal regulators in the course of
CKF The major problems are primarily renal anemia and renal bone disease (renal osteodystrophy)
Renal anemia
Renal anemia which is often associated with fatigue and cognitive and sexual dysfunction
has a significant impact on the quality of life of patients with CKF Anemia has also been identified
as an important etiologic factor in the development of left ventricular hypertrophy an independent
risk factor for heart failure and a predictor of mortality in HD patients (Golper et al 2003) The
major cause of renal anemia in CKF is an inadequate production of the glycoprotein hormone
erythropoietin (EPO) because of a reduction in functional kidney parenchyma (Santoro 2002)
Furthermore free radicals elicited from leucocytes by their contact with the dialysis membrane
cause hemolysis with consecutive anemia in CKF patients on extracorporeal renal replacement
therapy (Eiselt et al 1999)
There are a number of other metabolic derangements associated with uremia that can affect
the production and survival of red blood cells (eg some uremic toxins parathormone protein
malnutrition) (Golper et al 2003 Eschbach and Adamson 1985) The introduction of recombinant
human EPO (rHuEPO) has revolutionized the treatment of anemia in CKF The vast majority of
patients respond very well to treatment but 5ndash10 of patients show some resistance to rHuEPO
the most common causes of which are considered iron deficiency (Santoro 2002) and the
development of MICS (Kalantar-Zadeh et al 2003) The EPO hyporesponsiveness can further
worsen symptoms that decrease the quality of life such as an intolerance of physical work
deterioration of cognitive functions anorexia insomnia or depression These problems are partly
related to the deficit of L-carnitine in HD patients (dialysis-related carnitine disorder) This disorder
is a functional metabolic deficiency common in chronic HD patients and can have a negative impact
on erythrocyte production and survival Laboratory studies examining the influence of carnitine on
red blood cell function and clinical trials in HD patients support the use of L-carnitine in the setting
of rHuEPO hyporesponsiveness (Golper et al 2003)
Renal osteodystrophy
Renal osteodystrophy which is the term used to describe the skeletal abnormalities of many
CKD patients is a multifactorial disorder of bone remodeling It encompasses a heterogeneous
group of disorders from states of high bone turnover to states of low bone turnover High-turnover
bone disease or osteitis fibrosa represents the manifestations of secondary hyperparathyroidism
(SHPT) on bone Low bone turnover syndromes are represented by the increasingly prevalent
adynamic bone or less commonly by osteomalacia These disorders may occur in combination or
alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most
important factor which is probably responsible for SHPT development is a deficit of active vitamin
D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is
a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the
small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this
situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting
hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and
subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this
harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one
or more of them may predominate in a particular patient during the course of CKF much overlap
occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an
important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular
calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)
The treatment of vitamin D deficiency when present in CKD patients is warranted since such
therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of
20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by
supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended
daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in
stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in
dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the
serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used
to treat vitamin D deficiency (National Kidney Foundation 2004)
Cardiovascular disease
CVD is the leading cause of death in patients with CKF For every registry reporting national
dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD
(Foley et al 1998) In comparison with the general population dialysis patients have a greater than
20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these
deaths are related to vascular occlusive disease with associated myocardial infarction
cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with
CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis
and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion
to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin
The evidence suggests that the damage is already far progressed when patients reach ESRD thus
effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with
albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional
risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential
(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)
recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin
concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than
1 g of protein24 hours (National Kidney Foundation 2002)
The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL
cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)
However as mentioned above some CKD patients with the lowest cholesterol levels are the most
likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac
risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)
Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism
uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et
al 1999)
Oxidative stress
Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds
the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly
reactive substances with an unpaired electron in the outer orbital and other related reactive
compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and
nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998
Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and
consequently are not recognized by cell LDL receptors They are subsequently accumulated in the
blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of
atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications
(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of
chronic inflammation) Free radicals originate from leucocytes which are activated during the
contact with the dialysis membrane and also from erythrocyte iron released as a consequence of
hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of
EPO treatment can also contribute to oxidative stress increasing free radical production by the so-
called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of
mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions
to more dangerous Fe(II) compounds (Eiselt et al 2006)
Dialysis-related amyloidosis
Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal
replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA
Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel
syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular
pathogenesis of this complication remains unknown Recent studies however have suggested a
pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased
carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in
uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation
end-product production Thus uremia might be a state of carbonyl overload with potentially
damaging proteins (carbonyl stress) (Miyata et al 1999)
Hyperhomocysteinemia and endothelial dysfunction
Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma
concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The
causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a
result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is
considered to be an independent risk factor for the development of CVD As mentioned above
reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased
Hcy levels appear to be paradoxically associated with a better clinical outcome The development of
MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration
is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy
was inversely correlated with subjective global nutritional assessment and positively correlated with
serum albumin and protein intake Thus serum albumin concentration is a strong determinant of
plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished
patients (Suliman et al 2001)
On the other hand the toxicity of Hcy results from the structural modification of proteins and
DNA Disruption of DNA methylation has been demonstrated to occur as a result of
hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a
principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may
impair endothelial function by the generation of oxygen species and decreased NO bioavailability
Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system
in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic
et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis
endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation
(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of
the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise
mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function
in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation
of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing
connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly
by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are
elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)
In some studies an increased level of ADMA has been identified as an independent predictor of
mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function
in CRF may offer a novel strategy to reduce CVD
Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately
it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney
Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with
risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years
and family history of CKD When CKD is detected an attempt should be made to identify and treat
the underlying conditions as well as the secondary abnormalities These goals include slowing
disease progression detecting and treating complications and managing cardiovascular risk factors
Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition
anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase
balance At the same time it is necessary to continue research projects focused on other areas that
may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas
include the development of MICS management of oxidative stress and endothelium protection
Clearly progress in management of CVD in patients with CKD will require collaboration with
experts in the research and treatment of vascular disease
Conclusion
CKD leading to CKF is an urgent medical problem in the context of demographic trends In
addition to the basic kidney disease many metabolic disorders develop in the course of CKF
Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment
decreases the accumulation of metabolites however it contributes to a deficit of some important
metabolic regulators and to the development of a chronic inflammation state These factors can lead
to serious secondary complications in CKF including atherosclerosis and related cardiovascular
disease malnutrition anemia renal bone disease and other problems These complications
markedly and negatively affect the prognosis and quality of life of patients with CKF and increase
costs for their treatment The prognosis of CKD patients can be improved if kidney disease is
diagnosed early and properly cured inclusive of the secondary complications Appropriate
treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and
hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for
kidney disease and to develop new therapeutic methods to improve the quality of life of CKD
patients At the same time we must try to reduce economic costs connected with treatment
Acknowledgments
This work was supported by the research project MSM 0021620819
References
ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52
1997
ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am
J Kidney Dis 21 573-592 1993
CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal
failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005
DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33
2005
DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several
potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003
DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of
chronic kidney disease Hemodial Int 10 42-48 2006
DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic
predialysis and hemodialysis patients J Nephrol 17 813-818 2004
DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P
PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and
hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001
DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte
defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66
76-80 1994
EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on
oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in
Press
EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy
Vnitr Lek 45 319-324 1999
ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985
FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M
GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential
hypertension N Engl J Med 317 350-357 1987
FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in
chronic renal disease Am J Kidney Dis 32 S112-S119 1998
GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular
calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005
GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the
risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004
GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J
Kidney Dis 41 (4 Suppl 4) S27-S34 2003
GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193
2001
GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-
carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis
patients Contrib Nephrol 98 36-43 1992
IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity
with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study
Kidney Int 55 1945-1951 1999
IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic
dialysis patients Semin Dial 17 471-478 2004
KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-
inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis
42 864-881 2003
KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M
COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation
Curr Opin Clin Nutr Metab Care 8 388-396 2005
KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON
DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health
Perspect 1 289-295 1998
KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997
KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J
Kidney Dis 24 1002-1009 1994
KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed
patients Am J Nephrol 23 158-164 2003
KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and
treatment Am J Kidney Dis 45 978-993 2005
KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A
MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an
independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up
J Am Soc Nephrol 10 1027-1036 1999
LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D
HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney
disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney
Int 67 2089-2100 2005
LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial
Transplant 14 828-833 1999
LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving
intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
and prealbumin concentrations) (Ikizler 2004) Urinary losses of protein and losses of amino acids
during a dialysis session may play a role as well Metabolic acidosis is an important factor that
markedly contributes to negative nitrogen and total body protein balance in CKF (Kovacic et al
2003 Mehrotra et al 2003) It has been demonstrated that the presence of uremic malnutrition
increases mortality and morbidity in chronic dialysis patients (Kopple 1994 Ikizler et al 1999) It
is very often combined with a chronic inflammation state in the syndrome known as MICS
(Kalantar-Zadeh et al 2003)
Carbohydrate metabolism
Disorders of carbohydrate metabolism are also very frequent in CKD Diabetics represent
about 35 of all patients on dialysis therapy Generally non-diabetic CKD patients often also have
glucose intolerance probably because of peripheral insulin resistance (Alvestrand 1997) Insulin
resistance is primarily detectable when the GFR is below 50 mlmin Reduced insulin-mediated
non-oxidative glucose disposal is the most evident defect of glucose metabolism but impairments
of glucose oxidation the defective suppression of endogenous glucose production and abnormal
insulin secretion also contribute to uremic glucose intolerance (Rigalleau and Gin 2005)
Accumulating nitrogenous uremic toxins seem to be the dominant cause of a specific defect in
insulin action and identification of these toxins is progressing particularly in the field of
carbamoylated amino acids The consequences of CKF such as exercise intolerance anemia
metabolic acidosis secondary hyperparathyroidism or vitamin D deficiency also indirectly play a
role (Rigalleau and Gin 2005 Rasic-Milutinovic et al 2000) It has been reported that insulin
resistance may be related to arterial hypertension (Ferrannini et al 1987) and may contribute to
high cardiovascular morbidity and mortality in patients with CKF (Shoji et al 2001 Shinohara et
al 2002) The underlying mechanism can be an impaired synthesis of nitric oxide (NO) in
endothelium of patients with CKD It was reported that appropriately functioning endothelial NO
synthase (eNOS) is important for the control not only of arterial pressure but also of glucose and
lipid homeostasis (Duplain et al 2001)
Lipid metabolism
Serum triglycerides (TG) are elevated in CKF because of enhanced production of TG-rich
lipoproteins such as very-low-density lipoproteins (VLDL) in the liver (Attman et al 1993) and
also because of dysfunction of TG degradation resulting from insufficient mitochondrial beta-
oxidation of fatty acids It can be caused by a deficit of L-carnitine which is frequently present
especially in hemodialysis (HD) patients (Cibulka et al 2005 Guarnieri et al 1992)
Hyperinsulinemia is the main factor increasing synthesis of TG and also directly decreases activity
of lipoprotein lipase The following changes in lipid metabolism are also found in many patients
with CKF The most prominent are increased serum TG levels and low levels of high-density
lipoprotein (HDL) cholesterol Low-density lipoprotein (LDL) cholesterol levels are often normal
but the cholesterol may originate from the atherogenic small and dense LDL subclass The
apolipoprotein B-containing part of the lipoprotein may undergo modifications (peptide
modification of the enzymatic and advanced glycation end-product oxidation or glycation)
Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote
prolonged circulation HDL particles are structurally altered during states of inflammation The
contribution of this complex and the atherogenic form of dyslipidemia to cardiovascular disease
(CVD) in patients with renal disease is at present unclear
Some studies report negative results regarding the predictive power of serum lipids for the
development of CVD (Wanner and Krane 2002) Recent findings have suggested that the
development of MICS is responsible for this phenomenon Because MICS leads to a low body mass
index hypocholesterolemia hypocreatininemia hypohomocysteinemia and other manifestations a
reverse epidemiology of traditional cardiovascular risk factors occurs in CKF Therefore
hypercholesterolemia obesity and increased blood levels of creatinine and homocysteine appear to
be protective and paradoxically associated with a better outcome in patients with CKF (Kalantar-
Zadeh et al 2003 Kalantar-Zadeh et al 2005)
It is well known that HDL cholesterol levels are inversely correlated with the risk of
atherosclerosis In addition to its role in reverse cholesterol transport HDL has the ability to protect
LDL particles against oxidation The underlying mechanism by which HDL inhibits LDL oxidation
is partly enzymatic There is increasing evidence that paraoxonase 1 (PON1) could be involved in
this process (Mackness et al 1993) It was proved that serum PON1 activity is reduced in CKF
patients The possible causes can include reduced HDL levels altered HDL subfraction distribution
reduced PON1 concentration and different PON1 phenotype distributions Another possible
explanation could be that PON1 activity is inhibited in the uremic environment Generally reduced
serum PON1 activity could also contribute to the accelerated development of atherosclerosis in
CKF patients (Dirican et al 2004)
Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for atherosclerotic
CVD It was found to be consistently elevated in a considerable proportion of CKD patients Plasma
concentrations of Lp(a) are highly heritable and mainly determined by a size polymorphism of
apolipoprotein(a) [Apo(a)] It has been demonstrated that the low-molecular-weight Apo(a)
phenotype independently predicted coronary artery disease occurrence in a cohort of 440 unselected
HD patients in a prospective study over five years (Kronenberg et al 1999) It has been suggested
that the Apo(a) size and the Lp(a) plasma concentration may play a synergistic role in advanced
atherosclerosis
Because kidneys perform important hormonal functions there are also some serious
complications associated with a lack of important metabolic hormonal regulators in the course of
CKF The major problems are primarily renal anemia and renal bone disease (renal osteodystrophy)
Renal anemia
Renal anemia which is often associated with fatigue and cognitive and sexual dysfunction
has a significant impact on the quality of life of patients with CKF Anemia has also been identified
as an important etiologic factor in the development of left ventricular hypertrophy an independent
risk factor for heart failure and a predictor of mortality in HD patients (Golper et al 2003) The
major cause of renal anemia in CKF is an inadequate production of the glycoprotein hormone
erythropoietin (EPO) because of a reduction in functional kidney parenchyma (Santoro 2002)
Furthermore free radicals elicited from leucocytes by their contact with the dialysis membrane
cause hemolysis with consecutive anemia in CKF patients on extracorporeal renal replacement
therapy (Eiselt et al 1999)
There are a number of other metabolic derangements associated with uremia that can affect
the production and survival of red blood cells (eg some uremic toxins parathormone protein
malnutrition) (Golper et al 2003 Eschbach and Adamson 1985) The introduction of recombinant
human EPO (rHuEPO) has revolutionized the treatment of anemia in CKF The vast majority of
patients respond very well to treatment but 5ndash10 of patients show some resistance to rHuEPO
the most common causes of which are considered iron deficiency (Santoro 2002) and the
development of MICS (Kalantar-Zadeh et al 2003) The EPO hyporesponsiveness can further
worsen symptoms that decrease the quality of life such as an intolerance of physical work
deterioration of cognitive functions anorexia insomnia or depression These problems are partly
related to the deficit of L-carnitine in HD patients (dialysis-related carnitine disorder) This disorder
is a functional metabolic deficiency common in chronic HD patients and can have a negative impact
on erythrocyte production and survival Laboratory studies examining the influence of carnitine on
red blood cell function and clinical trials in HD patients support the use of L-carnitine in the setting
of rHuEPO hyporesponsiveness (Golper et al 2003)
Renal osteodystrophy
Renal osteodystrophy which is the term used to describe the skeletal abnormalities of many
CKD patients is a multifactorial disorder of bone remodeling It encompasses a heterogeneous
group of disorders from states of high bone turnover to states of low bone turnover High-turnover
bone disease or osteitis fibrosa represents the manifestations of secondary hyperparathyroidism
(SHPT) on bone Low bone turnover syndromes are represented by the increasingly prevalent
adynamic bone or less commonly by osteomalacia These disorders may occur in combination or
alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most
important factor which is probably responsible for SHPT development is a deficit of active vitamin
D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is
a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the
small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this
situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting
hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and
subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this
harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one
or more of them may predominate in a particular patient during the course of CKF much overlap
occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an
important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular
calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)
The treatment of vitamin D deficiency when present in CKD patients is warranted since such
therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of
20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by
supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended
daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in
stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in
dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the
serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used
to treat vitamin D deficiency (National Kidney Foundation 2004)
Cardiovascular disease
CVD is the leading cause of death in patients with CKF For every registry reporting national
dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD
(Foley et al 1998) In comparison with the general population dialysis patients have a greater than
20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these
deaths are related to vascular occlusive disease with associated myocardial infarction
cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with
CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis
and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion
to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin
The evidence suggests that the damage is already far progressed when patients reach ESRD thus
effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with
albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional
risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential
(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)
recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin
concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than
1 g of protein24 hours (National Kidney Foundation 2002)
The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL
cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)
However as mentioned above some CKD patients with the lowest cholesterol levels are the most
likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac
risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)
Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism
uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et
al 1999)
Oxidative stress
Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds
the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly
reactive substances with an unpaired electron in the outer orbital and other related reactive
compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and
nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998
Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and
consequently are not recognized by cell LDL receptors They are subsequently accumulated in the
blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of
atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications
(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of
chronic inflammation) Free radicals originate from leucocytes which are activated during the
contact with the dialysis membrane and also from erythrocyte iron released as a consequence of
hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of
EPO treatment can also contribute to oxidative stress increasing free radical production by the so-
called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of
mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions
to more dangerous Fe(II) compounds (Eiselt et al 2006)
Dialysis-related amyloidosis
Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal
replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA
Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel
syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular
pathogenesis of this complication remains unknown Recent studies however have suggested a
pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased
carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in
uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation
end-product production Thus uremia might be a state of carbonyl overload with potentially
damaging proteins (carbonyl stress) (Miyata et al 1999)
Hyperhomocysteinemia and endothelial dysfunction
Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma
concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The
causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a
result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is
considered to be an independent risk factor for the development of CVD As mentioned above
reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased
Hcy levels appear to be paradoxically associated with a better clinical outcome The development of
MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration
is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy
was inversely correlated with subjective global nutritional assessment and positively correlated with
serum albumin and protein intake Thus serum albumin concentration is a strong determinant of
plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished
patients (Suliman et al 2001)
On the other hand the toxicity of Hcy results from the structural modification of proteins and
DNA Disruption of DNA methylation has been demonstrated to occur as a result of
hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a
principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may
impair endothelial function by the generation of oxygen species and decreased NO bioavailability
Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system
in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic
et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis
endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation
(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of
the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise
mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function
in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation
of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing
connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly
by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are
elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)
In some studies an increased level of ADMA has been identified as an independent predictor of
mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function
in CRF may offer a novel strategy to reduce CVD
Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately
it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney
Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with
risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years
and family history of CKD When CKD is detected an attempt should be made to identify and treat
the underlying conditions as well as the secondary abnormalities These goals include slowing
disease progression detecting and treating complications and managing cardiovascular risk factors
Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition
anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase
balance At the same time it is necessary to continue research projects focused on other areas that
may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas
include the development of MICS management of oxidative stress and endothelium protection
Clearly progress in management of CVD in patients with CKD will require collaboration with
experts in the research and treatment of vascular disease
Conclusion
CKD leading to CKF is an urgent medical problem in the context of demographic trends In
addition to the basic kidney disease many metabolic disorders develop in the course of CKF
Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment
decreases the accumulation of metabolites however it contributes to a deficit of some important
metabolic regulators and to the development of a chronic inflammation state These factors can lead
to serious secondary complications in CKF including atherosclerosis and related cardiovascular
disease malnutrition anemia renal bone disease and other problems These complications
markedly and negatively affect the prognosis and quality of life of patients with CKF and increase
costs for their treatment The prognosis of CKD patients can be improved if kidney disease is
diagnosed early and properly cured inclusive of the secondary complications Appropriate
treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and
hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for
kidney disease and to develop new therapeutic methods to improve the quality of life of CKD
patients At the same time we must try to reduce economic costs connected with treatment
Acknowledgments
This work was supported by the research project MSM 0021620819
References
ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52
1997
ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am
J Kidney Dis 21 573-592 1993
CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal
failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005
DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33
2005
DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several
potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003
DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of
chronic kidney disease Hemodial Int 10 42-48 2006
DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic
predialysis and hemodialysis patients J Nephrol 17 813-818 2004
DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P
PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and
hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001
DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte
defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66
76-80 1994
EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on
oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in
Press
EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy
Vnitr Lek 45 319-324 1999
ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985
FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M
GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential
hypertension N Engl J Med 317 350-357 1987
FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in
chronic renal disease Am J Kidney Dis 32 S112-S119 1998
GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular
calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005
GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the
risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004
GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J
Kidney Dis 41 (4 Suppl 4) S27-S34 2003
GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193
2001
GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-
carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis
patients Contrib Nephrol 98 36-43 1992
IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity
with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study
Kidney Int 55 1945-1951 1999
IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic
dialysis patients Semin Dial 17 471-478 2004
KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-
inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis
42 864-881 2003
KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M
COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation
Curr Opin Clin Nutr Metab Care 8 388-396 2005
KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON
DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health
Perspect 1 289-295 1998
KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997
KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J
Kidney Dis 24 1002-1009 1994
KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed
patients Am J Nephrol 23 158-164 2003
KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and
treatment Am J Kidney Dis 45 978-993 2005
KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A
MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an
independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up
J Am Soc Nephrol 10 1027-1036 1999
LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D
HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney
disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney
Int 67 2089-2100 2005
LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial
Transplant 14 828-833 1999
LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving
intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
Lipid metabolism
Serum triglycerides (TG) are elevated in CKF because of enhanced production of TG-rich
lipoproteins such as very-low-density lipoproteins (VLDL) in the liver (Attman et al 1993) and
also because of dysfunction of TG degradation resulting from insufficient mitochondrial beta-
oxidation of fatty acids It can be caused by a deficit of L-carnitine which is frequently present
especially in hemodialysis (HD) patients (Cibulka et al 2005 Guarnieri et al 1992)
Hyperinsulinemia is the main factor increasing synthesis of TG and also directly decreases activity
of lipoprotein lipase The following changes in lipid metabolism are also found in many patients
with CKF The most prominent are increased serum TG levels and low levels of high-density
lipoprotein (HDL) cholesterol Low-density lipoprotein (LDL) cholesterol levels are often normal
but the cholesterol may originate from the atherogenic small and dense LDL subclass The
apolipoprotein B-containing part of the lipoprotein may undergo modifications (peptide
modification of the enzymatic and advanced glycation end-product oxidation or glycation)
Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote
prolonged circulation HDL particles are structurally altered during states of inflammation The
contribution of this complex and the atherogenic form of dyslipidemia to cardiovascular disease
(CVD) in patients with renal disease is at present unclear
Some studies report negative results regarding the predictive power of serum lipids for the
development of CVD (Wanner and Krane 2002) Recent findings have suggested that the
development of MICS is responsible for this phenomenon Because MICS leads to a low body mass
index hypocholesterolemia hypocreatininemia hypohomocysteinemia and other manifestations a
reverse epidemiology of traditional cardiovascular risk factors occurs in CKF Therefore
hypercholesterolemia obesity and increased blood levels of creatinine and homocysteine appear to
be protective and paradoxically associated with a better outcome in patients with CKF (Kalantar-
Zadeh et al 2003 Kalantar-Zadeh et al 2005)
It is well known that HDL cholesterol levels are inversely correlated with the risk of
atherosclerosis In addition to its role in reverse cholesterol transport HDL has the ability to protect
LDL particles against oxidation The underlying mechanism by which HDL inhibits LDL oxidation
is partly enzymatic There is increasing evidence that paraoxonase 1 (PON1) could be involved in
this process (Mackness et al 1993) It was proved that serum PON1 activity is reduced in CKF
patients The possible causes can include reduced HDL levels altered HDL subfraction distribution
reduced PON1 concentration and different PON1 phenotype distributions Another possible
explanation could be that PON1 activity is inhibited in the uremic environment Generally reduced
serum PON1 activity could also contribute to the accelerated development of atherosclerosis in
CKF patients (Dirican et al 2004)
Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for atherosclerotic
CVD It was found to be consistently elevated in a considerable proportion of CKD patients Plasma
concentrations of Lp(a) are highly heritable and mainly determined by a size polymorphism of
apolipoprotein(a) [Apo(a)] It has been demonstrated that the low-molecular-weight Apo(a)
phenotype independently predicted coronary artery disease occurrence in a cohort of 440 unselected
HD patients in a prospective study over five years (Kronenberg et al 1999) It has been suggested
that the Apo(a) size and the Lp(a) plasma concentration may play a synergistic role in advanced
atherosclerosis
Because kidneys perform important hormonal functions there are also some serious
complications associated with a lack of important metabolic hormonal regulators in the course of
CKF The major problems are primarily renal anemia and renal bone disease (renal osteodystrophy)
Renal anemia
Renal anemia which is often associated with fatigue and cognitive and sexual dysfunction
has a significant impact on the quality of life of patients with CKF Anemia has also been identified
as an important etiologic factor in the development of left ventricular hypertrophy an independent
risk factor for heart failure and a predictor of mortality in HD patients (Golper et al 2003) The
major cause of renal anemia in CKF is an inadequate production of the glycoprotein hormone
erythropoietin (EPO) because of a reduction in functional kidney parenchyma (Santoro 2002)
Furthermore free radicals elicited from leucocytes by their contact with the dialysis membrane
cause hemolysis with consecutive anemia in CKF patients on extracorporeal renal replacement
therapy (Eiselt et al 1999)
There are a number of other metabolic derangements associated with uremia that can affect
the production and survival of red blood cells (eg some uremic toxins parathormone protein
malnutrition) (Golper et al 2003 Eschbach and Adamson 1985) The introduction of recombinant
human EPO (rHuEPO) has revolutionized the treatment of anemia in CKF The vast majority of
patients respond very well to treatment but 5ndash10 of patients show some resistance to rHuEPO
the most common causes of which are considered iron deficiency (Santoro 2002) and the
development of MICS (Kalantar-Zadeh et al 2003) The EPO hyporesponsiveness can further
worsen symptoms that decrease the quality of life such as an intolerance of physical work
deterioration of cognitive functions anorexia insomnia or depression These problems are partly
related to the deficit of L-carnitine in HD patients (dialysis-related carnitine disorder) This disorder
is a functional metabolic deficiency common in chronic HD patients and can have a negative impact
on erythrocyte production and survival Laboratory studies examining the influence of carnitine on
red blood cell function and clinical trials in HD patients support the use of L-carnitine in the setting
of rHuEPO hyporesponsiveness (Golper et al 2003)
Renal osteodystrophy
Renal osteodystrophy which is the term used to describe the skeletal abnormalities of many
CKD patients is a multifactorial disorder of bone remodeling It encompasses a heterogeneous
group of disorders from states of high bone turnover to states of low bone turnover High-turnover
bone disease or osteitis fibrosa represents the manifestations of secondary hyperparathyroidism
(SHPT) on bone Low bone turnover syndromes are represented by the increasingly prevalent
adynamic bone or less commonly by osteomalacia These disorders may occur in combination or
alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most
important factor which is probably responsible for SHPT development is a deficit of active vitamin
D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is
a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the
small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this
situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting
hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and
subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this
harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one
or more of them may predominate in a particular patient during the course of CKF much overlap
occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an
important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular
calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)
The treatment of vitamin D deficiency when present in CKD patients is warranted since such
therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of
20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by
supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended
daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in
stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in
dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the
serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used
to treat vitamin D deficiency (National Kidney Foundation 2004)
Cardiovascular disease
CVD is the leading cause of death in patients with CKF For every registry reporting national
dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD
(Foley et al 1998) In comparison with the general population dialysis patients have a greater than
20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these
deaths are related to vascular occlusive disease with associated myocardial infarction
cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with
CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis
and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion
to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin
The evidence suggests that the damage is already far progressed when patients reach ESRD thus
effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with
albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional
risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential
(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)
recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin
concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than
1 g of protein24 hours (National Kidney Foundation 2002)
The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL
cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)
However as mentioned above some CKD patients with the lowest cholesterol levels are the most
likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac
risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)
Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism
uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et
al 1999)
Oxidative stress
Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds
the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly
reactive substances with an unpaired electron in the outer orbital and other related reactive
compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and
nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998
Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and
consequently are not recognized by cell LDL receptors They are subsequently accumulated in the
blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of
atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications
(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of
chronic inflammation) Free radicals originate from leucocytes which are activated during the
contact with the dialysis membrane and also from erythrocyte iron released as a consequence of
hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of
EPO treatment can also contribute to oxidative stress increasing free radical production by the so-
called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of
mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions
to more dangerous Fe(II) compounds (Eiselt et al 2006)
Dialysis-related amyloidosis
Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal
replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA
Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel
syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular
pathogenesis of this complication remains unknown Recent studies however have suggested a
pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased
carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in
uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation
end-product production Thus uremia might be a state of carbonyl overload with potentially
damaging proteins (carbonyl stress) (Miyata et al 1999)
Hyperhomocysteinemia and endothelial dysfunction
Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma
concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The
causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a
result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is
considered to be an independent risk factor for the development of CVD As mentioned above
reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased
Hcy levels appear to be paradoxically associated with a better clinical outcome The development of
MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration
is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy
was inversely correlated with subjective global nutritional assessment and positively correlated with
serum albumin and protein intake Thus serum albumin concentration is a strong determinant of
plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished
patients (Suliman et al 2001)
On the other hand the toxicity of Hcy results from the structural modification of proteins and
DNA Disruption of DNA methylation has been demonstrated to occur as a result of
hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a
principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may
impair endothelial function by the generation of oxygen species and decreased NO bioavailability
Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system
in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic
et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis
endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation
(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of
the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise
mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function
in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation
of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing
connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly
by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are
elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)
In some studies an increased level of ADMA has been identified as an independent predictor of
mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function
in CRF may offer a novel strategy to reduce CVD
Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately
it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney
Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with
risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years
and family history of CKD When CKD is detected an attempt should be made to identify and treat
the underlying conditions as well as the secondary abnormalities These goals include slowing
disease progression detecting and treating complications and managing cardiovascular risk factors
Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition
anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase
balance At the same time it is necessary to continue research projects focused on other areas that
may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas
include the development of MICS management of oxidative stress and endothelium protection
Clearly progress in management of CVD in patients with CKD will require collaboration with
experts in the research and treatment of vascular disease
Conclusion
CKD leading to CKF is an urgent medical problem in the context of demographic trends In
addition to the basic kidney disease many metabolic disorders develop in the course of CKF
Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment
decreases the accumulation of metabolites however it contributes to a deficit of some important
metabolic regulators and to the development of a chronic inflammation state These factors can lead
to serious secondary complications in CKF including atherosclerosis and related cardiovascular
disease malnutrition anemia renal bone disease and other problems These complications
markedly and negatively affect the prognosis and quality of life of patients with CKF and increase
costs for their treatment The prognosis of CKD patients can be improved if kidney disease is
diagnosed early and properly cured inclusive of the secondary complications Appropriate
treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and
hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for
kidney disease and to develop new therapeutic methods to improve the quality of life of CKD
patients At the same time we must try to reduce economic costs connected with treatment
Acknowledgments
This work was supported by the research project MSM 0021620819
References
ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52
1997
ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am
J Kidney Dis 21 573-592 1993
CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal
failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005
DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33
2005
DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several
potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003
DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of
chronic kidney disease Hemodial Int 10 42-48 2006
DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic
predialysis and hemodialysis patients J Nephrol 17 813-818 2004
DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P
PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and
hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001
DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte
defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66
76-80 1994
EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on
oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in
Press
EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy
Vnitr Lek 45 319-324 1999
ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985
FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M
GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential
hypertension N Engl J Med 317 350-357 1987
FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in
chronic renal disease Am J Kidney Dis 32 S112-S119 1998
GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular
calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005
GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the
risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004
GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J
Kidney Dis 41 (4 Suppl 4) S27-S34 2003
GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193
2001
GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-
carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis
patients Contrib Nephrol 98 36-43 1992
IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity
with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study
Kidney Int 55 1945-1951 1999
IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic
dialysis patients Semin Dial 17 471-478 2004
KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-
inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis
42 864-881 2003
KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M
COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation
Curr Opin Clin Nutr Metab Care 8 388-396 2005
KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON
DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health
Perspect 1 289-295 1998
KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997
KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J
Kidney Dis 24 1002-1009 1994
KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed
patients Am J Nephrol 23 158-164 2003
KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and
treatment Am J Kidney Dis 45 978-993 2005
KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A
MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an
independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up
J Am Soc Nephrol 10 1027-1036 1999
LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D
HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney
disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney
Int 67 2089-2100 2005
LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial
Transplant 14 828-833 1999
LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving
intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
It is well known that HDL cholesterol levels are inversely correlated with the risk of
atherosclerosis In addition to its role in reverse cholesterol transport HDL has the ability to protect
LDL particles against oxidation The underlying mechanism by which HDL inhibits LDL oxidation
is partly enzymatic There is increasing evidence that paraoxonase 1 (PON1) could be involved in
this process (Mackness et al 1993) It was proved that serum PON1 activity is reduced in CKF
patients The possible causes can include reduced HDL levels altered HDL subfraction distribution
reduced PON1 concentration and different PON1 phenotype distributions Another possible
explanation could be that PON1 activity is inhibited in the uremic environment Generally reduced
serum PON1 activity could also contribute to the accelerated development of atherosclerosis in
CKF patients (Dirican et al 2004)
Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for atherosclerotic
CVD It was found to be consistently elevated in a considerable proportion of CKD patients Plasma
concentrations of Lp(a) are highly heritable and mainly determined by a size polymorphism of
apolipoprotein(a) [Apo(a)] It has been demonstrated that the low-molecular-weight Apo(a)
phenotype independently predicted coronary artery disease occurrence in a cohort of 440 unselected
HD patients in a prospective study over five years (Kronenberg et al 1999) It has been suggested
that the Apo(a) size and the Lp(a) plasma concentration may play a synergistic role in advanced
atherosclerosis
Because kidneys perform important hormonal functions there are also some serious
complications associated with a lack of important metabolic hormonal regulators in the course of
CKF The major problems are primarily renal anemia and renal bone disease (renal osteodystrophy)
Renal anemia
Renal anemia which is often associated with fatigue and cognitive and sexual dysfunction
has a significant impact on the quality of life of patients with CKF Anemia has also been identified
as an important etiologic factor in the development of left ventricular hypertrophy an independent
risk factor for heart failure and a predictor of mortality in HD patients (Golper et al 2003) The
major cause of renal anemia in CKF is an inadequate production of the glycoprotein hormone
erythropoietin (EPO) because of a reduction in functional kidney parenchyma (Santoro 2002)
Furthermore free radicals elicited from leucocytes by their contact with the dialysis membrane
cause hemolysis with consecutive anemia in CKF patients on extracorporeal renal replacement
therapy (Eiselt et al 1999)
There are a number of other metabolic derangements associated with uremia that can affect
the production and survival of red blood cells (eg some uremic toxins parathormone protein
malnutrition) (Golper et al 2003 Eschbach and Adamson 1985) The introduction of recombinant
human EPO (rHuEPO) has revolutionized the treatment of anemia in CKF The vast majority of
patients respond very well to treatment but 5ndash10 of patients show some resistance to rHuEPO
the most common causes of which are considered iron deficiency (Santoro 2002) and the
development of MICS (Kalantar-Zadeh et al 2003) The EPO hyporesponsiveness can further
worsen symptoms that decrease the quality of life such as an intolerance of physical work
deterioration of cognitive functions anorexia insomnia or depression These problems are partly
related to the deficit of L-carnitine in HD patients (dialysis-related carnitine disorder) This disorder
is a functional metabolic deficiency common in chronic HD patients and can have a negative impact
on erythrocyte production and survival Laboratory studies examining the influence of carnitine on
red blood cell function and clinical trials in HD patients support the use of L-carnitine in the setting
of rHuEPO hyporesponsiveness (Golper et al 2003)
Renal osteodystrophy
Renal osteodystrophy which is the term used to describe the skeletal abnormalities of many
CKD patients is a multifactorial disorder of bone remodeling It encompasses a heterogeneous
group of disorders from states of high bone turnover to states of low bone turnover High-turnover
bone disease or osteitis fibrosa represents the manifestations of secondary hyperparathyroidism
(SHPT) on bone Low bone turnover syndromes are represented by the increasingly prevalent
adynamic bone or less commonly by osteomalacia These disorders may occur in combination or
alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most
important factor which is probably responsible for SHPT development is a deficit of active vitamin
D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is
a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the
small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this
situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting
hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and
subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this
harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one
or more of them may predominate in a particular patient during the course of CKF much overlap
occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an
important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular
calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)
The treatment of vitamin D deficiency when present in CKD patients is warranted since such
therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of
20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by
supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended
daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in
stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in
dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the
serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used
to treat vitamin D deficiency (National Kidney Foundation 2004)
Cardiovascular disease
CVD is the leading cause of death in patients with CKF For every registry reporting national
dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD
(Foley et al 1998) In comparison with the general population dialysis patients have a greater than
20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these
deaths are related to vascular occlusive disease with associated myocardial infarction
cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with
CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis
and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion
to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin
The evidence suggests that the damage is already far progressed when patients reach ESRD thus
effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with
albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional
risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential
(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)
recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin
concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than
1 g of protein24 hours (National Kidney Foundation 2002)
The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL
cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)
However as mentioned above some CKD patients with the lowest cholesterol levels are the most
likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac
risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)
Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism
uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et
al 1999)
Oxidative stress
Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds
the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly
reactive substances with an unpaired electron in the outer orbital and other related reactive
compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and
nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998
Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and
consequently are not recognized by cell LDL receptors They are subsequently accumulated in the
blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of
atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications
(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of
chronic inflammation) Free radicals originate from leucocytes which are activated during the
contact with the dialysis membrane and also from erythrocyte iron released as a consequence of
hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of
EPO treatment can also contribute to oxidative stress increasing free radical production by the so-
called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of
mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions
to more dangerous Fe(II) compounds (Eiselt et al 2006)
Dialysis-related amyloidosis
Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal
replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA
Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel
syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular
pathogenesis of this complication remains unknown Recent studies however have suggested a
pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased
carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in
uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation
end-product production Thus uremia might be a state of carbonyl overload with potentially
damaging proteins (carbonyl stress) (Miyata et al 1999)
Hyperhomocysteinemia and endothelial dysfunction
Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma
concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The
causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a
result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is
considered to be an independent risk factor for the development of CVD As mentioned above
reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased
Hcy levels appear to be paradoxically associated with a better clinical outcome The development of
MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration
is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy
was inversely correlated with subjective global nutritional assessment and positively correlated with
serum albumin and protein intake Thus serum albumin concentration is a strong determinant of
plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished
patients (Suliman et al 2001)
On the other hand the toxicity of Hcy results from the structural modification of proteins and
DNA Disruption of DNA methylation has been demonstrated to occur as a result of
hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a
principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may
impair endothelial function by the generation of oxygen species and decreased NO bioavailability
Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system
in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic
et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis
endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation
(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of
the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise
mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function
in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation
of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing
connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly
by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are
elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)
In some studies an increased level of ADMA has been identified as an independent predictor of
mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function
in CRF may offer a novel strategy to reduce CVD
Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately
it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney
Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with
risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years
and family history of CKD When CKD is detected an attempt should be made to identify and treat
the underlying conditions as well as the secondary abnormalities These goals include slowing
disease progression detecting and treating complications and managing cardiovascular risk factors
Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition
anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase
balance At the same time it is necessary to continue research projects focused on other areas that
may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas
include the development of MICS management of oxidative stress and endothelium protection
Clearly progress in management of CVD in patients with CKD will require collaboration with
experts in the research and treatment of vascular disease
Conclusion
CKD leading to CKF is an urgent medical problem in the context of demographic trends In
addition to the basic kidney disease many metabolic disorders develop in the course of CKF
Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment
decreases the accumulation of metabolites however it contributes to a deficit of some important
metabolic regulators and to the development of a chronic inflammation state These factors can lead
to serious secondary complications in CKF including atherosclerosis and related cardiovascular
disease malnutrition anemia renal bone disease and other problems These complications
markedly and negatively affect the prognosis and quality of life of patients with CKF and increase
costs for their treatment The prognosis of CKD patients can be improved if kidney disease is
diagnosed early and properly cured inclusive of the secondary complications Appropriate
treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and
hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for
kidney disease and to develop new therapeutic methods to improve the quality of life of CKD
patients At the same time we must try to reduce economic costs connected with treatment
Acknowledgments
This work was supported by the research project MSM 0021620819
References
ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52
1997
ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am
J Kidney Dis 21 573-592 1993
CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal
failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005
DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33
2005
DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several
potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003
DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of
chronic kidney disease Hemodial Int 10 42-48 2006
DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic
predialysis and hemodialysis patients J Nephrol 17 813-818 2004
DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P
PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and
hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001
DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte
defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66
76-80 1994
EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on
oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in
Press
EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy
Vnitr Lek 45 319-324 1999
ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985
FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M
GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential
hypertension N Engl J Med 317 350-357 1987
FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in
chronic renal disease Am J Kidney Dis 32 S112-S119 1998
GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular
calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005
GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the
risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004
GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J
Kidney Dis 41 (4 Suppl 4) S27-S34 2003
GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193
2001
GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-
carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis
patients Contrib Nephrol 98 36-43 1992
IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity
with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study
Kidney Int 55 1945-1951 1999
IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic
dialysis patients Semin Dial 17 471-478 2004
KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-
inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis
42 864-881 2003
KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M
COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation
Curr Opin Clin Nutr Metab Care 8 388-396 2005
KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON
DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health
Perspect 1 289-295 1998
KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997
KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J
Kidney Dis 24 1002-1009 1994
KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed
patients Am J Nephrol 23 158-164 2003
KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and
treatment Am J Kidney Dis 45 978-993 2005
KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A
MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an
independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up
J Am Soc Nephrol 10 1027-1036 1999
LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D
HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney
disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney
Int 67 2089-2100 2005
LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial
Transplant 14 828-833 1999
LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving
intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
major cause of renal anemia in CKF is an inadequate production of the glycoprotein hormone
erythropoietin (EPO) because of a reduction in functional kidney parenchyma (Santoro 2002)
Furthermore free radicals elicited from leucocytes by their contact with the dialysis membrane
cause hemolysis with consecutive anemia in CKF patients on extracorporeal renal replacement
therapy (Eiselt et al 1999)
There are a number of other metabolic derangements associated with uremia that can affect
the production and survival of red blood cells (eg some uremic toxins parathormone protein
malnutrition) (Golper et al 2003 Eschbach and Adamson 1985) The introduction of recombinant
human EPO (rHuEPO) has revolutionized the treatment of anemia in CKF The vast majority of
patients respond very well to treatment but 5ndash10 of patients show some resistance to rHuEPO
the most common causes of which are considered iron deficiency (Santoro 2002) and the
development of MICS (Kalantar-Zadeh et al 2003) The EPO hyporesponsiveness can further
worsen symptoms that decrease the quality of life such as an intolerance of physical work
deterioration of cognitive functions anorexia insomnia or depression These problems are partly
related to the deficit of L-carnitine in HD patients (dialysis-related carnitine disorder) This disorder
is a functional metabolic deficiency common in chronic HD patients and can have a negative impact
on erythrocyte production and survival Laboratory studies examining the influence of carnitine on
red blood cell function and clinical trials in HD patients support the use of L-carnitine in the setting
of rHuEPO hyporesponsiveness (Golper et al 2003)
Renal osteodystrophy
Renal osteodystrophy which is the term used to describe the skeletal abnormalities of many
CKD patients is a multifactorial disorder of bone remodeling It encompasses a heterogeneous
group of disorders from states of high bone turnover to states of low bone turnover High-turnover
bone disease or osteitis fibrosa represents the manifestations of secondary hyperparathyroidism
(SHPT) on bone Low bone turnover syndromes are represented by the increasingly prevalent
adynamic bone or less commonly by osteomalacia These disorders may occur in combination or
alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most
important factor which is probably responsible for SHPT development is a deficit of active vitamin
D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is
a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the
small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this
situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting
hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and
subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this
harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one
or more of them may predominate in a particular patient during the course of CKF much overlap
occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an
important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular
calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)
The treatment of vitamin D deficiency when present in CKD patients is warranted since such
therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of
20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by
supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended
daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in
stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in
dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the
serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used
to treat vitamin D deficiency (National Kidney Foundation 2004)
Cardiovascular disease
CVD is the leading cause of death in patients with CKF For every registry reporting national
dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD
(Foley et al 1998) In comparison with the general population dialysis patients have a greater than
20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these
deaths are related to vascular occlusive disease with associated myocardial infarction
cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with
CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis
and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion
to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin
The evidence suggests that the damage is already far progressed when patients reach ESRD thus
effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with
albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional
risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential
(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)
recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin
concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than
1 g of protein24 hours (National Kidney Foundation 2002)
The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL
cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)
However as mentioned above some CKD patients with the lowest cholesterol levels are the most
likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac
risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)
Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism
uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et
al 1999)
Oxidative stress
Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds
the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly
reactive substances with an unpaired electron in the outer orbital and other related reactive
compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and
nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998
Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and
consequently are not recognized by cell LDL receptors They are subsequently accumulated in the
blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of
atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications
(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of
chronic inflammation) Free radicals originate from leucocytes which are activated during the
contact with the dialysis membrane and also from erythrocyte iron released as a consequence of
hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of
EPO treatment can also contribute to oxidative stress increasing free radical production by the so-
called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of
mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions
to more dangerous Fe(II) compounds (Eiselt et al 2006)
Dialysis-related amyloidosis
Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal
replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA
Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel
syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular
pathogenesis of this complication remains unknown Recent studies however have suggested a
pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased
carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in
uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation
end-product production Thus uremia might be a state of carbonyl overload with potentially
damaging proteins (carbonyl stress) (Miyata et al 1999)
Hyperhomocysteinemia and endothelial dysfunction
Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma
concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The
causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a
result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is
considered to be an independent risk factor for the development of CVD As mentioned above
reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased
Hcy levels appear to be paradoxically associated with a better clinical outcome The development of
MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration
is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy
was inversely correlated with subjective global nutritional assessment and positively correlated with
serum albumin and protein intake Thus serum albumin concentration is a strong determinant of
plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished
patients (Suliman et al 2001)
On the other hand the toxicity of Hcy results from the structural modification of proteins and
DNA Disruption of DNA methylation has been demonstrated to occur as a result of
hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a
principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may
impair endothelial function by the generation of oxygen species and decreased NO bioavailability
Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system
in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic
et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis
endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation
(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of
the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise
mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function
in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation
of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing
connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly
by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are
elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)
In some studies an increased level of ADMA has been identified as an independent predictor of
mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function
in CRF may offer a novel strategy to reduce CVD
Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately
it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney
Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with
risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years
and family history of CKD When CKD is detected an attempt should be made to identify and treat
the underlying conditions as well as the secondary abnormalities These goals include slowing
disease progression detecting and treating complications and managing cardiovascular risk factors
Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition
anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase
balance At the same time it is necessary to continue research projects focused on other areas that
may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas
include the development of MICS management of oxidative stress and endothelium protection
Clearly progress in management of CVD in patients with CKD will require collaboration with
experts in the research and treatment of vascular disease
Conclusion
CKD leading to CKF is an urgent medical problem in the context of demographic trends In
addition to the basic kidney disease many metabolic disorders develop in the course of CKF
Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment
decreases the accumulation of metabolites however it contributes to a deficit of some important
metabolic regulators and to the development of a chronic inflammation state These factors can lead
to serious secondary complications in CKF including atherosclerosis and related cardiovascular
disease malnutrition anemia renal bone disease and other problems These complications
markedly and negatively affect the prognosis and quality of life of patients with CKF and increase
costs for their treatment The prognosis of CKD patients can be improved if kidney disease is
diagnosed early and properly cured inclusive of the secondary complications Appropriate
treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and
hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for
kidney disease and to develop new therapeutic methods to improve the quality of life of CKD
patients At the same time we must try to reduce economic costs connected with treatment
Acknowledgments
This work was supported by the research project MSM 0021620819
References
ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52
1997
ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am
J Kidney Dis 21 573-592 1993
CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal
failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005
DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33
2005
DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several
potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003
DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of
chronic kidney disease Hemodial Int 10 42-48 2006
DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic
predialysis and hemodialysis patients J Nephrol 17 813-818 2004
DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P
PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and
hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001
DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte
defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66
76-80 1994
EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on
oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in
Press
EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy
Vnitr Lek 45 319-324 1999
ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985
FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M
GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential
hypertension N Engl J Med 317 350-357 1987
FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in
chronic renal disease Am J Kidney Dis 32 S112-S119 1998
GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular
calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005
GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the
risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004
GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J
Kidney Dis 41 (4 Suppl 4) S27-S34 2003
GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193
2001
GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-
carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis
patients Contrib Nephrol 98 36-43 1992
IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity
with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study
Kidney Int 55 1945-1951 1999
IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic
dialysis patients Semin Dial 17 471-478 2004
KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-
inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis
42 864-881 2003
KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M
COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation
Curr Opin Clin Nutr Metab Care 8 388-396 2005
KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON
DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health
Perspect 1 289-295 1998
KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997
KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J
Kidney Dis 24 1002-1009 1994
KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed
patients Am J Nephrol 23 158-164 2003
KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and
treatment Am J Kidney Dis 45 978-993 2005
KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A
MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an
independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up
J Am Soc Nephrol 10 1027-1036 1999
LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D
HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney
disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney
Int 67 2089-2100 2005
LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial
Transplant 14 828-833 1999
LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving
intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most
important factor which is probably responsible for SHPT development is a deficit of active vitamin
D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is
a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the
small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this
situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting
hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and
subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this
harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one
or more of them may predominate in a particular patient during the course of CKF much overlap
occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an
important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular
calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)
The treatment of vitamin D deficiency when present in CKD patients is warranted since such
therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of
20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by
supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended
daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in
stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in
dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the
serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used
to treat vitamin D deficiency (National Kidney Foundation 2004)
Cardiovascular disease
CVD is the leading cause of death in patients with CKF For every registry reporting national
dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD
(Foley et al 1998) In comparison with the general population dialysis patients have a greater than
20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these
deaths are related to vascular occlusive disease with associated myocardial infarction
cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with
CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis
and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion
to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin
The evidence suggests that the damage is already far progressed when patients reach ESRD thus
effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with
albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional
risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential
(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)
recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin
concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than
1 g of protein24 hours (National Kidney Foundation 2002)
The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL
cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)
However as mentioned above some CKD patients with the lowest cholesterol levels are the most
likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac
risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)
Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism
uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et
al 1999)
Oxidative stress
Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds
the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly
reactive substances with an unpaired electron in the outer orbital and other related reactive
compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and
nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998
Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and
consequently are not recognized by cell LDL receptors They are subsequently accumulated in the
blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of
atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications
(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of
chronic inflammation) Free radicals originate from leucocytes which are activated during the
contact with the dialysis membrane and also from erythrocyte iron released as a consequence of
hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of
EPO treatment can also contribute to oxidative stress increasing free radical production by the so-
called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of
mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions
to more dangerous Fe(II) compounds (Eiselt et al 2006)
Dialysis-related amyloidosis
Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal
replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA
Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel
syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular
pathogenesis of this complication remains unknown Recent studies however have suggested a
pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased
carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in
uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation
end-product production Thus uremia might be a state of carbonyl overload with potentially
damaging proteins (carbonyl stress) (Miyata et al 1999)
Hyperhomocysteinemia and endothelial dysfunction
Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma
concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The
causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a
result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is
considered to be an independent risk factor for the development of CVD As mentioned above
reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased
Hcy levels appear to be paradoxically associated with a better clinical outcome The development of
MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration
is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy
was inversely correlated with subjective global nutritional assessment and positively correlated with
serum albumin and protein intake Thus serum albumin concentration is a strong determinant of
plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished
patients (Suliman et al 2001)
On the other hand the toxicity of Hcy results from the structural modification of proteins and
DNA Disruption of DNA methylation has been demonstrated to occur as a result of
hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a
principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may
impair endothelial function by the generation of oxygen species and decreased NO bioavailability
Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system
in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic
et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis
endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation
(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of
the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise
mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function
in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation
of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing
connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly
by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are
elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)
In some studies an increased level of ADMA has been identified as an independent predictor of
mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function
in CRF may offer a novel strategy to reduce CVD
Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately
it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney
Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with
risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years
and family history of CKD When CKD is detected an attempt should be made to identify and treat
the underlying conditions as well as the secondary abnormalities These goals include slowing
disease progression detecting and treating complications and managing cardiovascular risk factors
Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition
anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase
balance At the same time it is necessary to continue research projects focused on other areas that
may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas
include the development of MICS management of oxidative stress and endothelium protection
Clearly progress in management of CVD in patients with CKD will require collaboration with
experts in the research and treatment of vascular disease
Conclusion
CKD leading to CKF is an urgent medical problem in the context of demographic trends In
addition to the basic kidney disease many metabolic disorders develop in the course of CKF
Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment
decreases the accumulation of metabolites however it contributes to a deficit of some important
metabolic regulators and to the development of a chronic inflammation state These factors can lead
to serious secondary complications in CKF including atherosclerosis and related cardiovascular
disease malnutrition anemia renal bone disease and other problems These complications
markedly and negatively affect the prognosis and quality of life of patients with CKF and increase
costs for their treatment The prognosis of CKD patients can be improved if kidney disease is
diagnosed early and properly cured inclusive of the secondary complications Appropriate
treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and
hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for
kidney disease and to develop new therapeutic methods to improve the quality of life of CKD
patients At the same time we must try to reduce economic costs connected with treatment
Acknowledgments
This work was supported by the research project MSM 0021620819
References
ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52
1997
ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am
J Kidney Dis 21 573-592 1993
CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal
failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005
DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33
2005
DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several
potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003
DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of
chronic kidney disease Hemodial Int 10 42-48 2006
DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic
predialysis and hemodialysis patients J Nephrol 17 813-818 2004
DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P
PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and
hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001
DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte
defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66
76-80 1994
EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on
oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in
Press
EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy
Vnitr Lek 45 319-324 1999
ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985
FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M
GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential
hypertension N Engl J Med 317 350-357 1987
FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in
chronic renal disease Am J Kidney Dis 32 S112-S119 1998
GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular
calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005
GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the
risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004
GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J
Kidney Dis 41 (4 Suppl 4) S27-S34 2003
GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193
2001
GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-
carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis
patients Contrib Nephrol 98 36-43 1992
IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity
with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study
Kidney Int 55 1945-1951 1999
IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic
dialysis patients Semin Dial 17 471-478 2004
KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-
inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis
42 864-881 2003
KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M
COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation
Curr Opin Clin Nutr Metab Care 8 388-396 2005
KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON
DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health
Perspect 1 289-295 1998
KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997
KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J
Kidney Dis 24 1002-1009 1994
KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed
patients Am J Nephrol 23 158-164 2003
KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and
treatment Am J Kidney Dis 45 978-993 2005
KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A
MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an
independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up
J Am Soc Nephrol 10 1027-1036 1999
LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D
HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney
disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney
Int 67 2089-2100 2005
LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial
Transplant 14 828-833 1999
LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving
intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
(Foley et al 1998) In comparison with the general population dialysis patients have a greater than
20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these
deaths are related to vascular occlusive disease with associated myocardial infarction
cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with
CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis
and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion
to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin
The evidence suggests that the damage is already far progressed when patients reach ESRD thus
effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with
albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional
risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential
(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)
recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin
concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than
1 g of protein24 hours (National Kidney Foundation 2002)
The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL
cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)
However as mentioned above some CKD patients with the lowest cholesterol levels are the most
likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac
risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)
Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism
uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et
al 1999)
Oxidative stress
Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds
the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly
reactive substances with an unpaired electron in the outer orbital and other related reactive
compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and
nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998
Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and
consequently are not recognized by cell LDL receptors They are subsequently accumulated in the
blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of
atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications
(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of
chronic inflammation) Free radicals originate from leucocytes which are activated during the
contact with the dialysis membrane and also from erythrocyte iron released as a consequence of
hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of
EPO treatment can also contribute to oxidative stress increasing free radical production by the so-
called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of
mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions
to more dangerous Fe(II) compounds (Eiselt et al 2006)
Dialysis-related amyloidosis
Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal
replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA
Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel
syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular
pathogenesis of this complication remains unknown Recent studies however have suggested a
pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased
carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in
uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation
end-product production Thus uremia might be a state of carbonyl overload with potentially
damaging proteins (carbonyl stress) (Miyata et al 1999)
Hyperhomocysteinemia and endothelial dysfunction
Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma
concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The
causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a
result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is
considered to be an independent risk factor for the development of CVD As mentioned above
reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased
Hcy levels appear to be paradoxically associated with a better clinical outcome The development of
MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration
is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy
was inversely correlated with subjective global nutritional assessment and positively correlated with
serum albumin and protein intake Thus serum albumin concentration is a strong determinant of
plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished
patients (Suliman et al 2001)
On the other hand the toxicity of Hcy results from the structural modification of proteins and
DNA Disruption of DNA methylation has been demonstrated to occur as a result of
hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a
principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may
impair endothelial function by the generation of oxygen species and decreased NO bioavailability
Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system
in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic
et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis
endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation
(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of
the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise
mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function
in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation
of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing
connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly
by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are
elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)
In some studies an increased level of ADMA has been identified as an independent predictor of
mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function
in CRF may offer a novel strategy to reduce CVD
Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately
it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney
Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with
risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years
and family history of CKD When CKD is detected an attempt should be made to identify and treat
the underlying conditions as well as the secondary abnormalities These goals include slowing
disease progression detecting and treating complications and managing cardiovascular risk factors
Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition
anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase
balance At the same time it is necessary to continue research projects focused on other areas that
may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas
include the development of MICS management of oxidative stress and endothelium protection
Clearly progress in management of CVD in patients with CKD will require collaboration with
experts in the research and treatment of vascular disease
Conclusion
CKD leading to CKF is an urgent medical problem in the context of demographic trends In
addition to the basic kidney disease many metabolic disorders develop in the course of CKF
Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment
decreases the accumulation of metabolites however it contributes to a deficit of some important
metabolic regulators and to the development of a chronic inflammation state These factors can lead
to serious secondary complications in CKF including atherosclerosis and related cardiovascular
disease malnutrition anemia renal bone disease and other problems These complications
markedly and negatively affect the prognosis and quality of life of patients with CKF and increase
costs for their treatment The prognosis of CKD patients can be improved if kidney disease is
diagnosed early and properly cured inclusive of the secondary complications Appropriate
treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and
hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for
kidney disease and to develop new therapeutic methods to improve the quality of life of CKD
patients At the same time we must try to reduce economic costs connected with treatment
Acknowledgments
This work was supported by the research project MSM 0021620819
References
ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52
1997
ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am
J Kidney Dis 21 573-592 1993
CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal
failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005
DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33
2005
DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several
potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003
DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of
chronic kidney disease Hemodial Int 10 42-48 2006
DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic
predialysis and hemodialysis patients J Nephrol 17 813-818 2004
DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P
PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and
hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001
DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte
defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66
76-80 1994
EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on
oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in
Press
EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy
Vnitr Lek 45 319-324 1999
ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985
FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M
GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential
hypertension N Engl J Med 317 350-357 1987
FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in
chronic renal disease Am J Kidney Dis 32 S112-S119 1998
GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular
calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005
GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the
risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004
GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J
Kidney Dis 41 (4 Suppl 4) S27-S34 2003
GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193
2001
GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-
carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis
patients Contrib Nephrol 98 36-43 1992
IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity
with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study
Kidney Int 55 1945-1951 1999
IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic
dialysis patients Semin Dial 17 471-478 2004
KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-
inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis
42 864-881 2003
KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M
COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation
Curr Opin Clin Nutr Metab Care 8 388-396 2005
KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON
DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health
Perspect 1 289-295 1998
KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997
KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J
Kidney Dis 24 1002-1009 1994
KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed
patients Am J Nephrol 23 158-164 2003
KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and
treatment Am J Kidney Dis 45 978-993 2005
KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A
MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an
independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up
J Am Soc Nephrol 10 1027-1036 1999
LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D
HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney
disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney
Int 67 2089-2100 2005
LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial
Transplant 14 828-833 1999
LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving
intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
reactive substances with an unpaired electron in the outer orbital and other related reactive
compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and
nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998
Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and
consequently are not recognized by cell LDL receptors They are subsequently accumulated in the
blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of
atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications
(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of
chronic inflammation) Free radicals originate from leucocytes which are activated during the
contact with the dialysis membrane and also from erythrocyte iron released as a consequence of
hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of
EPO treatment can also contribute to oxidative stress increasing free radical production by the so-
called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of
mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions
to more dangerous Fe(II) compounds (Eiselt et al 2006)
Dialysis-related amyloidosis
Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal
replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA
Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel
syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular
pathogenesis of this complication remains unknown Recent studies however have suggested a
pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased
carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in
uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation
end-product production Thus uremia might be a state of carbonyl overload with potentially
damaging proteins (carbonyl stress) (Miyata et al 1999)
Hyperhomocysteinemia and endothelial dysfunction
Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma
concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The
causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a
result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is
considered to be an independent risk factor for the development of CVD As mentioned above
reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased
Hcy levels appear to be paradoxically associated with a better clinical outcome The development of
MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration
is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy
was inversely correlated with subjective global nutritional assessment and positively correlated with
serum albumin and protein intake Thus serum albumin concentration is a strong determinant of
plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished
patients (Suliman et al 2001)
On the other hand the toxicity of Hcy results from the structural modification of proteins and
DNA Disruption of DNA methylation has been demonstrated to occur as a result of
hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a
principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may
impair endothelial function by the generation of oxygen species and decreased NO bioavailability
Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system
in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic
et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis
endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation
(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of
the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise
mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function
in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation
of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing
connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly
by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are
elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)
In some studies an increased level of ADMA has been identified as an independent predictor of
mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function
in CRF may offer a novel strategy to reduce CVD
Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately
it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney
Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with
risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years
and family history of CKD When CKD is detected an attempt should be made to identify and treat
the underlying conditions as well as the secondary abnormalities These goals include slowing
disease progression detecting and treating complications and managing cardiovascular risk factors
Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition
anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase
balance At the same time it is necessary to continue research projects focused on other areas that
may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas
include the development of MICS management of oxidative stress and endothelium protection
Clearly progress in management of CVD in patients with CKD will require collaboration with
experts in the research and treatment of vascular disease
Conclusion
CKD leading to CKF is an urgent medical problem in the context of demographic trends In
addition to the basic kidney disease many metabolic disorders develop in the course of CKF
Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment
decreases the accumulation of metabolites however it contributes to a deficit of some important
metabolic regulators and to the development of a chronic inflammation state These factors can lead
to serious secondary complications in CKF including atherosclerosis and related cardiovascular
disease malnutrition anemia renal bone disease and other problems These complications
markedly and negatively affect the prognosis and quality of life of patients with CKF and increase
costs for their treatment The prognosis of CKD patients can be improved if kidney disease is
diagnosed early and properly cured inclusive of the secondary complications Appropriate
treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and
hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for
kidney disease and to develop new therapeutic methods to improve the quality of life of CKD
patients At the same time we must try to reduce economic costs connected with treatment
Acknowledgments
This work was supported by the research project MSM 0021620819
References
ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52
1997
ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am
J Kidney Dis 21 573-592 1993
CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal
failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005
DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33
2005
DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several
potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003
DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of
chronic kidney disease Hemodial Int 10 42-48 2006
DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic
predialysis and hemodialysis patients J Nephrol 17 813-818 2004
DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P
PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and
hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001
DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte
defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66
76-80 1994
EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on
oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in
Press
EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy
Vnitr Lek 45 319-324 1999
ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985
FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M
GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential
hypertension N Engl J Med 317 350-357 1987
FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in
chronic renal disease Am J Kidney Dis 32 S112-S119 1998
GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular
calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005
GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the
risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004
GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J
Kidney Dis 41 (4 Suppl 4) S27-S34 2003
GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193
2001
GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-
carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis
patients Contrib Nephrol 98 36-43 1992
IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity
with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study
Kidney Int 55 1945-1951 1999
IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic
dialysis patients Semin Dial 17 471-478 2004
KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-
inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis
42 864-881 2003
KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M
COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation
Curr Opin Clin Nutr Metab Care 8 388-396 2005
KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON
DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health
Perspect 1 289-295 1998
KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997
KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J
Kidney Dis 24 1002-1009 1994
KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed
patients Am J Nephrol 23 158-164 2003
KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and
treatment Am J Kidney Dis 45 978-993 2005
KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A
MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an
independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up
J Am Soc Nephrol 10 1027-1036 1999
LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D
HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney
disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney
Int 67 2089-2100 2005
LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial
Transplant 14 828-833 1999
LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving
intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
Hyperhomocysteinemia and endothelial dysfunction
Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma
concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The
causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a
result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is
considered to be an independent risk factor for the development of CVD As mentioned above
reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased
Hcy levels appear to be paradoxically associated with a better clinical outcome The development of
MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration
is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy
was inversely correlated with subjective global nutritional assessment and positively correlated with
serum albumin and protein intake Thus serum albumin concentration is a strong determinant of
plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished
patients (Suliman et al 2001)
On the other hand the toxicity of Hcy results from the structural modification of proteins and
DNA Disruption of DNA methylation has been demonstrated to occur as a result of
hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a
principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may
impair endothelial function by the generation of oxygen species and decreased NO bioavailability
Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system
in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic
et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis
endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation
(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of
the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise
mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function
in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation
of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing
connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly
by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are
elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)
In some studies an increased level of ADMA has been identified as an independent predictor of
mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function
in CRF may offer a novel strategy to reduce CVD
Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately
it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney
Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with
risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years
and family history of CKD When CKD is detected an attempt should be made to identify and treat
the underlying conditions as well as the secondary abnormalities These goals include slowing
disease progression detecting and treating complications and managing cardiovascular risk factors
Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition
anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase
balance At the same time it is necessary to continue research projects focused on other areas that
may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas
include the development of MICS management of oxidative stress and endothelium protection
Clearly progress in management of CVD in patients with CKD will require collaboration with
experts in the research and treatment of vascular disease
Conclusion
CKD leading to CKF is an urgent medical problem in the context of demographic trends In
addition to the basic kidney disease many metabolic disorders develop in the course of CKF
Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment
decreases the accumulation of metabolites however it contributes to a deficit of some important
metabolic regulators and to the development of a chronic inflammation state These factors can lead
to serious secondary complications in CKF including atherosclerosis and related cardiovascular
disease malnutrition anemia renal bone disease and other problems These complications
markedly and negatively affect the prognosis and quality of life of patients with CKF and increase
costs for their treatment The prognosis of CKD patients can be improved if kidney disease is
diagnosed early and properly cured inclusive of the secondary complications Appropriate
treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and
hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for
kidney disease and to develop new therapeutic methods to improve the quality of life of CKD
patients At the same time we must try to reduce economic costs connected with treatment
Acknowledgments
This work was supported by the research project MSM 0021620819
References
ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52
1997
ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am
J Kidney Dis 21 573-592 1993
CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal
failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005
DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33
2005
DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several
potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003
DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of
chronic kidney disease Hemodial Int 10 42-48 2006
DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic
predialysis and hemodialysis patients J Nephrol 17 813-818 2004
DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P
PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and
hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001
DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte
defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66
76-80 1994
EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on
oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in
Press
EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy
Vnitr Lek 45 319-324 1999
ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985
FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M
GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential
hypertension N Engl J Med 317 350-357 1987
FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in
chronic renal disease Am J Kidney Dis 32 S112-S119 1998
GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular
calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005
GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the
risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004
GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J
Kidney Dis 41 (4 Suppl 4) S27-S34 2003
GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193
2001
GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-
carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis
patients Contrib Nephrol 98 36-43 1992
IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity
with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study
Kidney Int 55 1945-1951 1999
IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic
dialysis patients Semin Dial 17 471-478 2004
KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-
inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis
42 864-881 2003
KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M
COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation
Curr Opin Clin Nutr Metab Care 8 388-396 2005
KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON
DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health
Perspect 1 289-295 1998
KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997
KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J
Kidney Dis 24 1002-1009 1994
KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed
patients Am J Nephrol 23 158-164 2003
KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and
treatment Am J Kidney Dis 45 978-993 2005
KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A
MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an
independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up
J Am Soc Nephrol 10 1027-1036 1999
LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D
HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney
disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney
Int 67 2089-2100 2005
LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial
Transplant 14 828-833 1999
LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving
intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation
of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing
connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly
by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are
elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)
In some studies an increased level of ADMA has been identified as an independent predictor of
mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function
in CRF may offer a novel strategy to reduce CVD
Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately
it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney
Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with
risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years
and family history of CKD When CKD is detected an attempt should be made to identify and treat
the underlying conditions as well as the secondary abnormalities These goals include slowing
disease progression detecting and treating complications and managing cardiovascular risk factors
Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition
anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase
balance At the same time it is necessary to continue research projects focused on other areas that
may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas
include the development of MICS management of oxidative stress and endothelium protection
Clearly progress in management of CVD in patients with CKD will require collaboration with
experts in the research and treatment of vascular disease
Conclusion
CKD leading to CKF is an urgent medical problem in the context of demographic trends In
addition to the basic kidney disease many metabolic disorders develop in the course of CKF
Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment
decreases the accumulation of metabolites however it contributes to a deficit of some important
metabolic regulators and to the development of a chronic inflammation state These factors can lead
to serious secondary complications in CKF including atherosclerosis and related cardiovascular
disease malnutrition anemia renal bone disease and other problems These complications
markedly and negatively affect the prognosis and quality of life of patients with CKF and increase
costs for their treatment The prognosis of CKD patients can be improved if kidney disease is
diagnosed early and properly cured inclusive of the secondary complications Appropriate
treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and
hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for
kidney disease and to develop new therapeutic methods to improve the quality of life of CKD
patients At the same time we must try to reduce economic costs connected with treatment
Acknowledgments
This work was supported by the research project MSM 0021620819
References
ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52
1997
ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am
J Kidney Dis 21 573-592 1993
CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal
failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005
DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33
2005
DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several
potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003
DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of
chronic kidney disease Hemodial Int 10 42-48 2006
DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic
predialysis and hemodialysis patients J Nephrol 17 813-818 2004
DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P
PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and
hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001
DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte
defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66
76-80 1994
EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on
oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in
Press
EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy
Vnitr Lek 45 319-324 1999
ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985
FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M
GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential
hypertension N Engl J Med 317 350-357 1987
FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in
chronic renal disease Am J Kidney Dis 32 S112-S119 1998
GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular
calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005
GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the
risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004
GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J
Kidney Dis 41 (4 Suppl 4) S27-S34 2003
GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193
2001
GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-
carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis
patients Contrib Nephrol 98 36-43 1992
IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity
with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study
Kidney Int 55 1945-1951 1999
IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic
dialysis patients Semin Dial 17 471-478 2004
KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-
inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis
42 864-881 2003
KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M
COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation
Curr Opin Clin Nutr Metab Care 8 388-396 2005
KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON
DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health
Perspect 1 289-295 1998
KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997
KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J
Kidney Dis 24 1002-1009 1994
KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed
patients Am J Nephrol 23 158-164 2003
KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and
treatment Am J Kidney Dis 45 978-993 2005
KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A
MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an
independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up
J Am Soc Nephrol 10 1027-1036 1999
LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D
HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney
disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney
Int 67 2089-2100 2005
LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial
Transplant 14 828-833 1999
LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving
intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
decreases the accumulation of metabolites however it contributes to a deficit of some important
metabolic regulators and to the development of a chronic inflammation state These factors can lead
to serious secondary complications in CKF including atherosclerosis and related cardiovascular
disease malnutrition anemia renal bone disease and other problems These complications
markedly and negatively affect the prognosis and quality of life of patients with CKF and increase
costs for their treatment The prognosis of CKD patients can be improved if kidney disease is
diagnosed early and properly cured inclusive of the secondary complications Appropriate
treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and
hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for
kidney disease and to develop new therapeutic methods to improve the quality of life of CKD
patients At the same time we must try to reduce economic costs connected with treatment
Acknowledgments
This work was supported by the research project MSM 0021620819
References
ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52
1997
ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am
J Kidney Dis 21 573-592 1993
CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal
failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005
DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33
2005
DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several
potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003
DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of
chronic kidney disease Hemodial Int 10 42-48 2006
DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic
predialysis and hemodialysis patients J Nephrol 17 813-818 2004
DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P
PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and
hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001
DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte
defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66
76-80 1994
EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on
oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in
Press
EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy
Vnitr Lek 45 319-324 1999
ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985
FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M
GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential
hypertension N Engl J Med 317 350-357 1987
FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in
chronic renal disease Am J Kidney Dis 32 S112-S119 1998
GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular
calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005
GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the
risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004
GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J
Kidney Dis 41 (4 Suppl 4) S27-S34 2003
GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193
2001
GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-
carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis
patients Contrib Nephrol 98 36-43 1992
IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity
with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study
Kidney Int 55 1945-1951 1999
IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic
dialysis patients Semin Dial 17 471-478 2004
KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-
inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis
42 864-881 2003
KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M
COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation
Curr Opin Clin Nutr Metab Care 8 388-396 2005
KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON
DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health
Perspect 1 289-295 1998
KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997
KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J
Kidney Dis 24 1002-1009 1994
KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed
patients Am J Nephrol 23 158-164 2003
KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and
treatment Am J Kidney Dis 45 978-993 2005
KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A
MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an
independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up
J Am Soc Nephrol 10 1027-1036 1999
LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D
HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney
disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney
Int 67 2089-2100 2005
LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial
Transplant 14 828-833 1999
LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving
intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
References
ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52
1997
ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am
J Kidney Dis 21 573-592 1993
CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal
failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005
DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33
2005
DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several
potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003
DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of
chronic kidney disease Hemodial Int 10 42-48 2006
DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic
predialysis and hemodialysis patients J Nephrol 17 813-818 2004
DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P
PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and
hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001
DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte
defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66
76-80 1994
EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on
oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in
Press
EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy
Vnitr Lek 45 319-324 1999
ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985
FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M
GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential
hypertension N Engl J Med 317 350-357 1987
FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in
chronic renal disease Am J Kidney Dis 32 S112-S119 1998
GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular
calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005
GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the
risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004
GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J
Kidney Dis 41 (4 Suppl 4) S27-S34 2003
GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193
2001
GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-
carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis
patients Contrib Nephrol 98 36-43 1992
IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity
with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study
Kidney Int 55 1945-1951 1999
IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic
dialysis patients Semin Dial 17 471-478 2004
KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-
inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis
42 864-881 2003
KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M
COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation
Curr Opin Clin Nutr Metab Care 8 388-396 2005
KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON
DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health
Perspect 1 289-295 1998
KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997
KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J
Kidney Dis 24 1002-1009 1994
KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed
patients Am J Nephrol 23 158-164 2003
KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and
treatment Am J Kidney Dis 45 978-993 2005
KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A
MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an
independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up
J Am Soc Nephrol 10 1027-1036 1999
LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D
HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney
disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney
Int 67 2089-2100 2005
LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial
Transplant 14 828-833 1999
LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving
intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985
FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M
GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential
hypertension N Engl J Med 317 350-357 1987
FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in
chronic renal disease Am J Kidney Dis 32 S112-S119 1998
GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular
calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005
GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the
risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004
GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J
Kidney Dis 41 (4 Suppl 4) S27-S34 2003
GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193
2001
GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-
carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis
patients Contrib Nephrol 98 36-43 1992
IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity
with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study
Kidney Int 55 1945-1951 1999
IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic
dialysis patients Semin Dial 17 471-478 2004
KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-
inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis
42 864-881 2003
KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M
COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation
Curr Opin Clin Nutr Metab Care 8 388-396 2005
KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON
DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health
Perspect 1 289-295 1998
KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997
KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J
Kidney Dis 24 1002-1009 1994
KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed
patients Am J Nephrol 23 158-164 2003
KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and
treatment Am J Kidney Dis 45 978-993 2005
KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A
MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an
independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up
J Am Soc Nephrol 10 1027-1036 1999
LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D
HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney
disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney
Int 67 2089-2100 2005
LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial
Transplant 14 828-833 1999
LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving
intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M
COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation
Curr Opin Clin Nutr Metab Care 8 388-396 2005
KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON
DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health
Perspect 1 289-295 1998
KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997
KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J
Kidney Dis 24 1002-1009 1994
KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed
patients Am J Nephrol 23 158-164 2003
KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and
treatment Am J Kidney Dis 45 978-993 2005
KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A
MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an
independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up
J Am Soc Nephrol 10 1027-1036 1999
LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D
HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney
disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney
Int 67 2089-2100 2005
LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial
Transplant 14 828-833 1999
LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving
intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in
prolonged maintance hemodialysis N Engl J Med 290 697-701 1974
LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE
NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of
inflammation and malnutrition JAMA 291 451-459 2004
LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal
osteodystrophy J Bone Miner Metab 24 169-171 2006
MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density
lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase
Atherosclerosis 104 129-135 1993
MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients
clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003
MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related
amyloidosis Miner Electrolyte Metab 25 114-117 1999
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease guideline 7 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney
disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266
2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm
NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing
dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at
httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm
NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular
dysfunction Postrad Med J 79 195-199 2003
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE
LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-
364 2004
PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D
Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med
43 1032-1038 2005
PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG
Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004
RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and
pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic
factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000
RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical
dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease
a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005
RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8
463-869 2005
SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002
SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T
TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular
mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002
SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H
ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular
mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001
SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15
(Suppl 5) 2-7 2000
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002
SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam
Physician 72 1723-1732 2005
SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic
renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med
39 734-738 2001
TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid
metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001
WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453
2002